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MOTTO studie


- candidate number29569
- NTR NumberNTR7580
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR20-sep-2018
- Secondary IDsNL67040.18.078 2018-002856-34
- Public TitleMOTTO studie
- Scientific TitleModifying tacrolimus related toxicity after liver transplantation. A randomized controlled trial comparing Envarsus® and Advagraf® in de novo liver transplant recipients.
- ACRONYMMOTTO
- hypothesisTo investigate whether Envarsus® leads to a significant reduction in new onset diabetes, chronic kidney disease and new onset hypertension.
- Healt Condition(s) or Problem(s) studiedLiver transplantation
- Inclusion criteria- First liver transplantation
- Age between 18 and 75
- Using immediate release tacrolimus
- written informed consent
- Female subject of childbearing potential must agree to practice effective birth control
- Exclusion criteria- Pregnancy or breast feeding
- eGFR < 30 mL/min/1.73m2
- Systemic infection
- Combined organ transplantation
- Use of a mTOR inhibitor
- Use of other tacrolimus formulations
- Hepatic artery trombosis
- Known allergy to the study drug or any of its components
- mec approval receivedno
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-dec-2018
- planned closingdate1-dec-2021
- Target number of participants106
- InterventionsAdvagraf of Envarsus
- Primary outcomeA composite endpoint of any of three events: sustained (>3 months post transplantation) new onset diabetes mellitus, eGFR < 60 ml/minute/1.73 m2 for >3 months or new onset hypertension.
- Secondary outcome- Drug compliance
- Quality of life
- Neurotoxicity in terms of tremors, cognitive impairment, sleep quality
- Pharmacokinetics and –dynamics
- Drug metabolism
- Liver steatosis and fibrosis
- Efficacy in terms of graft and patient survival and episodes of acute cellular rejection, chronic rejection, antibody mediated rejection
- TimepointsStart inclusion: 01 December 2018
End inclusion: 01 December 2020
Last patient last visit: 01 December 2021
Database closure: 31 August 2022
Final report: 31 December 2022
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIESDr. S. Darwish Murad
- CONTACT for SCIENTIFIC QUERIESDr. S. Darwish Murad
- Sponsor/Initiator Stichting Lever en Maag Darm onderzoek, Erasmus MC
- Funding
(Source(s) of Monetary or Material Support)
Chiesi Pharmaceutical
- Publications
- Brief summaryRationale:
Chronic use of tacrolimus is associated with significant side effects including new onset diabetes after transplantation (NODAT), renal impairment, hypertension, hyperlipidemia and tremor and other neurotoxic traits. It is known that toxicity of tacrolimus is (partly) related to higher peak serum blood concentrations in the first year after transplantation. Reducing peak levels without reducing effective inhibition of the immune response could therefore theoretically attenuate the toxic effects of tacrolimus. Envarsus®, a prolonged release formulation of tacrolimus which gives less fluctuation of whole-blood tacrolimus concentrations and requires lower dosage for similar systemic tacrolimus exposure has the potential to lower the toxic effects of tacrolimus and decrease the amount of metabolic side effects, as compared to the current standard, Advagraf®.

Objective: To investigate whether Envarsus® leads to a significant reduction in new onset diabetes, chronic kidney disease and new onset hypertension.

Study design: Randomized controlled two-arm phase 4 intervention trial comparing Envarsus® with the current standard treatment Advagraf® after liver transplantation.

Study population: De novo liver transplant recipients ≥18 year with a first liver transplant at the Erasmus MC University Medical Centre or Leiden University Medical Centre.

Intervention: At discharge post transplantation patients will be initiated on prolonged release tacrolimus, which, according to randomization, will either be standard Advagraf® or Envarsus®.

Main study parameters/endpoints: The primary endpoint is a composite endpoint of any of three events: sustained (>3 months post transplantation) new onset diabetes mellitus, eGFR < 60 ml/minute/1.73 m2 for >3 months or new onset hypertension. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Our study resembles our standard clinical practice in that recipients are always converted from an immediate release tacrolimus (i.e. Prograft®) to an extended release formulation (previously exclusively Advagraf®) at hospital discharge. Furthermore, the study visit schedule is an exact copy of our regular outpatient visit schedule posttransplantation and does not include any invasive interventions. All blood draws scheduled in this study are part of routine care. As extra diagnostics, patients at Erasmus MC will undergo a neuropsychological evaluation to assess compliance and signs of neurotoxicity and LUMC recipients will undergo area under the curve (AUC) measurements of tacrolimus, of whom the majority is done at home. Throughout the study participants will be closely (monthly) monitored for adequate tacrolimus exposure. As both tacrolimus formulations are approved for this indication and the active drug on both formulations is the same, this study is considered a low risk study. The anticipated benefit of this study is that it may lead to lowering of the metabolic side effects, nefrotoxicity and neurotoxicity of long term tacrolimus treatment. Thus, we believe that the benefit-risk assessment for this study is favourable
- Main changes (audit trail)
- RECORD20-sep-2018 - 9-nov-2018


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