Liver TransplantPhase 4NCT00260208
Liver Fibrosis in Patients Transplanted for Hepatitis C Receiving Either Cyclosporine Microemulsion or Tacrolimus
A Phase 4 study testing Cyclosporine A and Tacrolimus in people with Liver Transplant and Hepatitis C, run by Novartis Pharmaceuticals at 2 sites in 2 countries.
Trial summary
Following a transplant for hepatitis C cirrhosis, the infection comes back in 70-90% of cases and over time causes fibrosis and eventually cirrhosis of the new liver. The aim of this study was to see if the frequency of liver fibrosis was different with cyclosporine microemulsion than tacrolimus Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Liver Transplant, Hepatitis C
- What is being tested?
- Cyclosporine A and Tacrolimus
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 361 participants
- Where
- 2 sitesin 2 countries
- Study dates
- Jan 2006to Sep 2010
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Reason for transplant is end-stage liver disease due to hepatitis C cirrhosis
- Patients receiving a first liver transplant from a deceased or living donor
- Patients in whom biopsies will be possible
Who cannot join
- Recipients of a liver from an hepatitis C virus positive (HCV+), human immunodeficiency virus positive (HIV+) or hepatitis B virus positive (HBV+) donor
- Patients with any severe coexisting disease or suffering any unstable medical condition or co-infected with HBV or HIV
- Patients with co-existing alcoholic disease who have not been abstinent for at least 6 months
- Transplanted for liver cancer exceeding a pre-defined size
- Pregnant or nursing women
- Other protocol-defined inclusion/exclusion criteria may apply
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United States1 site
Novartis Investigative Site
East Hanover, New Jersey
About this study
Official title: A Multicenter, Randomized, Open-label Study to Compare the Development of Liver Fibrosis at 12 Months After Transplantation for Hepatitis C Cirrhosis in Patients Receiving Either Cyclosporine Microemulsion or Tacrolimus
Following a transplant for hepatitis C cirrhosis, the infection comes back in 70-90% of cases and over time causes fibrosis and eventually cirrhosis of the new liver. The aim of this study was to see if the frequency of liver fibrosis was different with cyclosporine microemulsion than tacrolimus
- Conditions
- Liver Transplant, Hepatitis C
- Being tested
- Cyclosporine A, Tacrolimus
- Keywords
- Liver transplant, adults, hepatitis C, liver fibrosis, cyclosporine microemulsion, tacrolimus
- Medical subject headings
- Hepatitis C, Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cyclosporine ADrug
Also called Neoral
Initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v.) within the first 24 hours post-transplantation.
TacrolimusDrug
Tacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses either orally or via a nasogastric (NG) tube or intravenously (i.v).
| Study group | Role | What they receive |
|---|---|---|
| Cyclosporin A | Active comparator | The first administration of Cyclosporin A (CsA) was within the first 24 hours post-transplantation at an initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout the study period. During the study, the dose of CsA was adjusted, as necessary, to achieve and maintain the C2 or C0 blood CsA concentration within the target ranges.
Before enrolling the first patient, each center chose the adjunct immunosuppressive (IS) regimen between:
* Steroids administered and tapered as per local practice
* interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice.
The regimen selected by the center was to be given to all patients enrolled in the trial from this center. Receives: Drug: Cyclosporine A |
| Tacrolimus | Active comparator | Tacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses (twice daily at 12-hour interval) either orally or via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout study period. Throughout the study, the dose of tacrolimus was adjusted as necessary to achieve and maintain C0 tacrolimus concentrations within target ranges.
Before enrolling the first patient, each center chose adjunct immunosuppressive (IS) regimen between:
* Steroids administered and tapered as per local practice
* interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice.
The regimen selected by center was to be given to all patients enrolled in trial from this center. Receives: Drug: Tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant
Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. Logistic regression on the presence of IK>=2 was applied based on central biopsy readings only.
Measured: 1 year post-transplant
Secondary outcomes (11)
Number of Participants With Combined Endpoint of Death or Graft Loss or Fibrosis Score (FS) ≥ 2
The number of participants with combined end point of death or graft loss or presented with a Ishak-Knodell fibrosis score (FS) ≥2 was calculated. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had liver retransplant or died. Assessment of hepatic fibrosis was performed with liver biopsies read centrally. Ishak-Knodell FS was used to stage liver disease; 0=none; 1=portal fibrosis (some); 2=portal fibrosis (most); 3=bridging fibrosis (few); 4=bridging fibrosis (many); 5=Incomplete cirrhosis; 6=cirrhosis. Higher score indicates greater fibrosis.
Measured: 1 year post-transplant
Number of Participants With Fibrosing Cholestatic Hepatitis
Fibrosing cholestatic hepatitis (FCH) is characterized by progressive jaundice with a rapid decline in liver function leading to liver failure, most often associated with markedly elevated viral levels detected in the bloodstream (e.g. more than 20 times pre-liver transplantation levels) and in the liver tissue as well. The presence of FCH was reported based on the diagnosis given by the investigator.
Measured: 1 year post-transplantation
Number of Participants With Death, Graft Loss, Death or Graft Loss, Graft Loss With Re-transplantation
Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.
Measured: 1 year post-transplant
Number of Participants With Treated Acute Rejection, Biopsy Proven Acute Rejection (BPAR), and Sub-clinical Rejection
Treated acute rejection is defined as an acute rejection, clinically suspected, whether biopsy-proven or not, which has been treated and confirmed by the investigator according to the response to therapy. BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. A sub-clinical rejection was defined as a rejection identified by center driven biopsy, i.e. a biopsy performed routinely at some pre-defined time points after transplantation as per center practice in the absence of any clinical signs of rejection.
Measured: 1 year post-transplant
Number of Participants With Combined Endpoint of Death or Graft Loss or Biopsy Proven Acute Rejection (BPAR)
BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.
Measured: 1 year post-transplant
Number of Participants With Death or Re-transplantation Due to Recurrence of Hepatitis C Cirrhosis
Cirrhosis was resulted due to the recurrence of the hepatitis C virus infection in the transplanted liver.
Measured: 1 year post-transplant
Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant (Intent to Treat Population)
Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis.
Measured: 1 year post-transplant
Mean Value of Liver Function Tests at 1 Year Post-transplantation
The mean value (in Units per liter, IU/L) of following tests were calculated at 1 year post-transplant:
- Serum glutamic pyruvic transaminase (SGPT)
- Serum Glutamic Oxaloacetic Transaminase (SGOT)
- Bilirubin
- Alkaline Phosphate
- γ-Glutamyltransferase (GGT)
Measured: 1 year post-transplant
Log-transformed Hepatitis C Virus Ribonucleic Acid (HCV RNA) Values up to 1 Year Post Transplant
HCV RNA was measured (IU/µL)centrally pre-transplant (Day 1) and at 48 hours (Day 3), Day 8 and 29, Month 6 and 12 post-transplant and concomitantly to any additional biopsies performed.
Measured: Pre-transplant (Day 1), Day , Day 8, Day 29, Month 6 and 12 post- transplant
Percentage of Participants With an Increase of at Least 1 Stage in Fibrosis
Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. An increase of at least 1 stage demonstrated a worsening of the disease, i.e. the transition from one score to the next higher one.
Measured: Between 1 and 2 years
Mean Fibrosis Score
Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. The mean score was equivalent to mean of IK at 1 and 2 years (evolution over time).
Measured: At 1and 2 years and its evolution over time
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Dec 2005 (estimated)
- Study startJan 2006
- Primary completionSep 2010
Why it stopped: Study was prematurely terminated due to poor recruitment.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Liver TransplantStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 361 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00260208
- Sponsor's protocol ID
- COLO400A2426
- Status last verified
- Dec 2011
- First submitted
- 30 Nov 2005
- Last updated
- 6 Dec 2011
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 6 Dec 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Randomized, Open-label Study to Compare the Development of Liver Fibrosis at 12 Months After Transplantation for Hepatitis C Cirrhosis in Patients Receiving Either Cyclosporine Microemulsion or Tacrolimus
- ClinicalTrials.gov ID
- NCT00260208
- Acronym / sponsor ID
- COLO400A2426
- Conditions
- Liver Transplant, Hepatitis C
- Keywords
- Liver transplant, adults, hepatitis C, liver fibrosis, cyclosporine microemulsion, tacrolimus
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study was prematurely terminated due to poor recruitment.
- Enrolment
- 361 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Jan 2006
- Primary completion
- Sep 2010 (actual)
- First posted
- 1 Dec 2005 (estimated)
- Results
- Posted 26 Oct 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Following a transplant for hepatitis C cirrhosis, the infection comes back in 70-90% of cases and over time causes fibrosis and eventually cirrhosis of the new liver. The aim of this study was to see if the frequency of liver fibrosis was different with cyclosporine microemulsion than tacrolimus
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cyclosporin A | Active comparator | Drug: Cyclosporine AThe first administration of Cyclosporin A (CsA) was within the first 24 hours post-transplantation at an initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout the study period. During the study, the dose of CsA was adjusted, as necessary, to achieve and maintain the C2 or C0 blood CsA concentration within the target ranges. Before enrolling the first patient, each center chose the adjunct immunosuppressive (IS) regimen between: * Steroids administered and tapered as per local practice * interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice. The regimen selected by the center was to be given to all patients enrolled in the trial from this center. |
| Tacrolimus | Active comparator | Drug: TacrolimusTacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses (twice daily at 12-hour interval) either orally or via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout study period. Throughout the study, the dose of tacrolimus was adjusted as necessary to achieve and maintain C0 tacrolimus concentrations within target ranges. Before enrolling the first patient, each center chose adjunct immunosuppressive (IS) regimen between: * Steroids administered and tapered as per local practice * interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice. The regimen selected by center was to be given to all patients enrolled in trial from this center. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Reason for transplant is end-stage liver disease due to hepatitis C cirrhosis
- Patients receiving a first liver transplant from a deceased or living donor
- Patients in whom biopsies will be possible
Key exclusion criteria (6 listed)
- Recipients of a liver from an hepatitis C virus positive (HCV+), human immunodeficiency virus positive (HIV+) or hepatitis B virus positive (HBV+) donor
- Patients with any severe coexisting disease or suffering any unstable medical condition or co-infected with HBV or HIV
- Patients with co-existing alcoholic disease who have not been abstinent for at least 6 months
- Transplanted for liver cancer exceeding a pre-defined size
- Pregnant or nursing women
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cyclosporine AAlso: NeoralInitial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v.) within the first 24 hours post-transplantation. | Drug | Cyclosporin A |
| TacrolimusTacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses either orally or via a nasogastric (NG) tube or intravenously (i.v). | Drug | Tacrolimus |
Primary outcome
Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant
Time frame: 1 year post-transplant
Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. Logistic regression on the presence of IK>=2 was applied based on central biopsy readings only.
11 secondary outcomes
Number of Participants With Combined Endpoint of Death or Graft Loss or Fibrosis Score (FS) ≥ 2
Time frame: 1 year post-transplant
Number of Participants With Fibrosing Cholestatic Hepatitis
Time frame: 1 year post-transplantation
Number of Participants With Death, Graft Loss, Death or Graft Loss, Graft Loss With Re-transplantation
Time frame: 1 year post-transplant
Number of Participants With Treated Acute Rejection, Biopsy Proven Acute Rejection (BPAR), and Sub-clinical Rejection
Time frame: 1 year post-transplant
Number of Participants With Combined Endpoint of Death or Graft Loss or Biopsy Proven Acute Rejection (BPAR)
Time frame: 1 year post-transplant
Number of Participants With Death or Re-transplantation Due to Recurrence of Hepatitis C Cirrhosis
Time frame: 1 year post-transplant
Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant (Intent to Treat Population)
Time frame: 1 year post-transplant
Mean Value of Liver Function Tests at 1 Year Post-transplantation
Time frame: 1 year post-transplant
Log-transformed Hepatitis C Virus Ribonucleic Acid (HCV RNA) Values up to 1 Year Post Transplant
Time frame: Pre-transplant (Day 1), Day , Day 8, Day 29, Month 6 and 12 post- transplant
Percentage of Participants With an Increase of at Least 1 Stage in Fibrosis
Time frame: Between 1 and 2 years
Mean Fibrosis Score
Time frame: At 1and 2 years and its evolution over time
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Dec 2011.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Cyclosporine A and Tacrolimus in people with Liver Transplant and Hepatitis C, run by Novartis Pharmaceuticals at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 6 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Oct 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant (time frame: 1 year post-transplant). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2011.