Liver DiseasePhase 4NCT01958190
Study Comparing in Livertransplantation Recipients With Tacrolimus Alone Versus Tacrolimus&Sirolimus
A Phase 4 study testing Tacrolimus and Sirolimus and Tacrolimus in people with Liver Disease, run by Foundation for Liver Research at 3 sites in Netherlands.
Trial summary
In this study we compare long term renal function in liver transplantation recipients treated with standard dose extended-release tacrolimus alone and recipients treated with a combination of low dose extended-release tacrolimus and low dose sirolimus. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Liver Disease
- What is being tested?
- Tacrolimus and Sirolimus and Tacrolimus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 196 participants
- Where
- 3 sitesNetherlands
- Study dates
- 7 Feb 2011to 20 May 2021
- Phase
- Phase 4
- Are there results?
- None posted in the registry
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 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Primary liver transplantation or retransplantation within 14 days after first transplantation
- Use of Advagraf at least 2 weeks prior to randomization
- Patent hepatic artery
- Closed abdominal wound
- Stable graft function
- Positive informed consent at time of randomization
- Age 18-70 years
Who cannot join
- Treatment with investigational drugs within 3 months before start of therapy
- Multi organ transplantation
- cGFR < 30 ml/min
- Proteinuria > 800 mg/24 h
- Hyperlipidemia refractory to optimal medical management (Cholesterol > 9 mmol/l and/or triglycerides > 8.5 mmol/l). Patients with controlled hyperlipidemia are acceptable at the time of randomization.
- Known hypersensitivity to sirolimus or its derivatives
Show all 17Show fewer
- Thrombocytes < 50 x 109 /L
- Leukocytes < 2.5 x 109 /L
- Haemoglobin < 6 mmol/L
- Biopsy proven rejection 2 weeks prior to randomization
- HIV positivity
- Signs of recurrent or de novo cancer
- Patients with non-HCC malignancies within the past 5 years (excluding successfully treated squamous cell carcinoma and basal cell carcinoma of the skin)
- Evidence of significant local or systemic infection
- Pregnancy or breast feeding
- Women of child-bearing potential not willing to take oral contraception
- Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study
Trial locations and contacts
3 sites in 1 country.
Netherlands3 sites
UMCG
Groningen, 9713 GZ
LUMC
Leiden, 2333 ZA
Erasmus Medical Center
Rotterdam, 3015CE
About this study
Official title: A Multicenter Randomized in Primary Livertransplantation Comparing Longterm Renal Function in Recipients Treated With Tacrolimus Alone and Recipients Treated With a Combination Tacrolimus and Sirolimus
In this study we compare long term renal function in liver transplantation recipients treated with standard dose extended-release tacrolimus alone and recipients treated with a combination of low dose extended-release tacrolimus and low dose sirolimus. The hypothesis is that the patients treated with the combination have better long term renal function than the patients treated with standard dose tacrolimus alone.
Read the detailed description
To evaluate the effectiveness and safety of concentration controlled combination of once daily dosed low-dose sirolimus (trough levels: 3-5 ng/ml) and extended-release tacrolimus (trough levels:3-5 ng/ml), in order to provide superior renal function while maintaining comparable rates of patient and graft survival, compared to concentration controlled once - daily extended release tacrolimus (trough levels: 5-10 ng/ml) at 12, 24 and 36 months post-transplant. Moreover, to compare the incidence of de novo malignancy, the quality of life, fatigue and side effects between both treatment arms.
2.1 Primary objectives: To evaluate the effectiveness and safety of concentration controlled combination of low-dose sirolimus (trough levels: 3-5 ng/ml) and extended-release tacrolimus (trough levels: 3-5 ng/ml), in order to provide superior renal function while maintaining comparable rates of patient and graft survival, compared to concentration controlled once - daily extended release tacrolimus (trough levels:-10 ng/ml) control at 12, 24 and 36 months post-transplant.
2.2. Secondary objectives:
- To compare the incidence of de novo and recurrence of cancer between study arm and control arm at 36 months.
- To compare the incidence and severity of biopsy proven acute rejection between study arm and control arm at 12, 24 and 36 months.
- To evaluate renal function at 12, 24 and 36 months (calculated GFR).
- To evaluate the development of new onset diabetes mellitus at 12, 24 and 36 months post transplant
- To evaluate the prevalence of CNI side effects at 12, 24 and 36 months
- To evaluate quality of life (Eq5D) and fatigue severity score at 12, 24 and 36 months
- To evaluate the percentage of patients on combination tacrolimus and sirolimus and converted back to tacrolimus mono-therapy.
- Conditions
- Liver Disease
- Being tested
- Tacrolimus and Sirolimus, Tacrolimus
- Keywords
- Liver transplantation long term renal function, tacrolimus sirolimus
- Medical subject headings
- Liver Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tacrolimus and SirolimusDrug
Also called Advagraf [Astellas Pharma bv), Rapamune
Arm 1 once daily combination therapy of normal dosed extended-release tacrolimus and prednisone for 3 months and monotherapy once daily extended-release tacrolimus thereafter up to 3 years after liver transplantation.
Arm 2 once daily combination therapy of low doses sirolimus and extended-release tacrolimus and prednisone for 3 months and combination therapy of low dose sirolimus and extended-release tacrolimus thereafter for up to 3 years after liver transplantation Continue Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician Conversion to sirolimus (3-5 ng/ml) and decrease Advagraf (3-5 ng/ml); 7.5 mg prednisone and lower or discontinue steroids after day 180 at the discretion of the treating physician
TacrolimusDrug
Also called Advagraf
Patient received standard-dose of Tracrolimus Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician
| Study group | Role | What they receive |
|---|---|---|
| Tacrolimus | Active comparator | Patient received standard-dose of Tracrolimus Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician Receives: Drug: Tacrolimus |
| combination Tacrolimus and Sirolimus | Experimental | Patients receive combination of low-dose extended release Tacrolimus and low-dose Sirolimus Receives: Drug: Tacrolimus and Sirolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Renal function
Percentage of patients with cGFR < 60ml/min
Measured: 3 years
Secondary outcomes (2)
Malignancies
number of de novo malignancies
Measured: 3 years
Diabetes Mellitus
Incidence of De novo diabetes mellitus
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Oct 2013 (estimated)
- Study start7 Feb 2011
- Primary completion20 May 2021
- Study completion20 May 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Liver DiseaseStudies of the same condition, open and under way.
- 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 196 participants (actual)
Sponsor and investigators
- Lead sponsor
- Foundation for Liver Research
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Herold J Metselaar, MD PhD, Principal investigator, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01958190
- Sponsor's protocol ID
- LOL-III-1
- Status last verified
- Mar 2022
- First submitted
- 27 Aug 2013
- Last updated
- 18 Mar 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 18 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter Randomized in Primary Livertransplantation Comparing Longterm Renal Function in Recipients Treated With Tacrolimus Alone and Recipients Treated With a Combination Tacrolimus and Sirolimus
- ClinicalTrials.gov ID
- NCT01958190
- Acronym / sponsor ID
- LOL-III-1
- Conditions
- Liver Disease
- Keywords
- Liver transplantation long term renal function, tacrolimus sirolimus
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 196 participants (actual)
- Lead sponsor
- Foundation for Liver ResearchUniversity, hospital or other
- Study start
- 7 Feb 2011 (actual)
- Primary completion
- 20 May 2021 (actual)
- Study completion
- 20 May 2021 (actual)
- First posted
- 9 Oct 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In this study we compare long term renal function in liver transplantation recipients treated with standard dose extended-release tacrolimus alone and recipients treated with a combination of low dose extended-release tacrolimus and low dose sirolimus. The hypothesis is that the patients treated with the combination have better long term renal function than the patients treated with standard dose tacrolimus alone.
Detailed description
To evaluate the effectiveness and safety of concentration controlled combination of once daily dosed low-dose sirolimus (trough levels: 3-5 ng/ml) and extended-release tacrolimus (trough levels:3-5 ng/ml), in order to provide superior renal function while maintaining comparable rates of patient and graft survival, compared to concentration controlled once - daily extended release tacrolimus (trough levels: 5-10 ng/ml) at 12, 24 and 36 months post-transplant. Moreover, to compare the incidence of de novo malignancy, the quality of life, fatigue and side effects between both treatment arms.
2.1 Primary objectives: To evaluate the effectiveness and safety of concentration controlled combination of low-dose sirolimus (trough levels: 3-5 ng/ml) and extended-release tacrolimus (trough levels: 3-5 ng/ml), in order to provide superior renal function while maintaining comparable rates of patient and graft survival, compared to concentration controlled once - daily extended release tacrolimus (trough levels:-10 ng/ml) control at 12, 24 and 36 months post-transplant.
2.2. Secondary objectives:
- To compare the incidence of de novo and recurrence of cancer between study arm and control arm at 36 months.
- To compare the incidence and severity of biopsy proven acute rejection between study arm and control arm at 12, 24 and 36 months.
- To evaluate renal function at 12, 24 and 36 months (calculated GFR).
- To evaluate the development of new onset diabetes mellitus at 12, 24 and 36 months post transplant
- To evaluate the prevalence of CNI side effects at 12, 24 and 36 months
- To evaluate quality of life (Eq5D) and fatigue severity score at 12, 24 and 36 months
- To evaluate the percentage of patients on combination tacrolimus and sirolimus and converted back to tacrolimus mono-therapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tacrolimus | Active comparator | Drug: TacrolimusPatient received standard-dose of Tracrolimus Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician |
| combination Tacrolimus and Sirolimus | Experimental | Drug: Tacrolimus and SirolimusPatients receive combination of low-dose extended release Tacrolimus and low-dose Sirolimus |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Primary liver transplantation or retransplantation within 14 days after first transplantation
- Use of Advagraf at least 2 weeks prior to randomization
- Patent hepatic artery
- Closed abdominal wound
- Stable graft function
Key exclusion criteria (17 listed)
- Treatment with investigational drugs within 3 months before start of therapy
- Multi organ transplantation
- cGFR < 30 ml/min
- Proteinuria > 800 mg/24 h
- Hyperlipidemia refractory to optimal medical management (Cholesterol > 9 mmol/l and/or triglycerides > 8.5 mmol/l). Patients with controlled hyperlipidemia are acceptable at the time of randomization.
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 |
|---|---|---|
| Tacrolimus and SirolimusAlso: Advagraf [Astellas Pharma bv), RapamuneArm 1 once daily combination therapy of normal dosed extended-release tacrolimus and prednisone for 3 months and monotherapy once daily extended-release tacrolimus thereafter up to 3 years after liver transplantation. Arm 2 once daily combination therapy of low doses sirolimus and extended-release tacrolimus and prednisone for 3 months and combination therapy of low dose sirolimus and extended-release tacrolimus thereafter for up to 3 years after liver transplantation Continue Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician Conversion to sirolimus (3-5 ng/ml) and decrease Advagraf (3-5 ng/ml); 7.5 mg prednisone and lower or discontinue steroids after day 180 at the discretion of the treating physician | Drug | combination Tacrolimus and Sirolimus |
| TacrolimusAlso: AdvagrafPatient received standard-dose of Tracrolimus Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician | Drug | Tacrolimus |
Primary outcome
Renal function
Time frame: 3 years
Percentage of patients with cGFR < 60ml/min
2 secondary outcomes
Malignancies
Time frame: 3 years
Diabetes Mellitus
Time frame: 3 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Mar 2022.
- Individual participant dataSharing planned: Undecided
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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.
Herold J Metselaar, MD PhD principal investigator
Erasmus Medical Center
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tacrolimus and Sirolimus and Tacrolimus in people with Liver Disease, run by Foundation for Liver Research at 3 sites in Netherlands.
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 7 inclusion and 17 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: finished, as of the sponsor's last update on 18 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Netherlands. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Renal function (time frame: 3 years). 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 18 Mar 2022.