*Randomized controlled prospEctiVe trial comparing extended-release with immediate-release tacrOlimus; reducing calcineurin inhibitor related toxicity in LUng TransplantatION patients*

Lung transplantation is a life-saving option in patients with end-stage lung
disease. The worldwide number of reported adult lung transplants in 2016 is
approximately 4500, an increasing performed procedure with improving survival
outcome. The median survival worldwide is 8,3 years Currently more than 350
lung transplant patients in follow-up at the University Medical Center
Groningen (UMCG), the largest lung transplant center of the Netherlands. The
median survival in the Netherlands and Belgium is approximately 11 years, which
is longer than the worldwide average probably due to concentrating transplant
care in large centers. The standard immunosuppressive regime in the UMCG for
lung transplantation has been prednisolone, IR tacrolimus (immediate-release
tacrolimus) and mycophenolic acid for over a decade. Before 2009 prednisolone,
tacrolimus and azathioprine was used.

Especially the introduction of the calcineurin inhibitor (CNI) tacrolimus,
showed reduction for both acute and chronic rejection. However, a drawback to
the administration of tacrolimus is its toxicity, particularly renal toxicity,
new onset diabetes mellitus after transplantation (NODAT), hypertension and
neurotoxicity. The International Society of Heart and Lung Transplantation
(ISHLT) report incidence of sever renal dysfunction defined as serum creatinine
> 221 µmol/L, dialysis or renal transplant of 11.4% after 2 years and 22,3% 5
years post lung transplantation. Renal function continues to deteriorate from
the moment patients are transplanted and receive immunosuppressant*s. In lung
transplant recipients the incidence of hypertension and NODAT is 23% and
19.8%-23% after 1 year and 50% and 34.4%-40% after 5 years. Tremor is one of
the most common CNI induced neurological toxic effect, besides polyneuropathy,
headaches, insomnia, vertigo, dysesthesia and reduced cognitive ability. These
side effects are attributed to high peak serum levels, whereas the
effectiveness of the drug is determined by the area under the curve. In general
lung transplant recipients have higher peak and trough levels when compared to
other solid organ transplant recipients and therefore potentially experience
more severe toxic side effects.

Because chronic renal failure is associated with an elevated risk of death
after transplantation, accurate renal function estimation and acknowledging
risk factors for developing renal failure are of uppermost importance.
Glomerular Filtration Rate (GFR) is generally accepted as the best overall
index of kidney function. Creatinine based formulas are commonly used in daily
practice for calculating estimated GFR (eGFR). In solid organ transplantation,
and especially in lung transplant recipients, creatinine based estimation of
GFR is less precise than in other populations. Reduced muscle mass and thereby
reduced creatinine generation is a major cause. Cystatin C is an alternative
filtration marker not under the influence of muscle mass, sex or age. Equations
using cystatin C perform better in estimating GFR in lung and other solid organ
transplantation.

Recently the new once daily calcineurin inhibitor LCP tacrolimus has been
introduced as immune suppressant in solid organ transplantation. The advantage
of LCP tacrolimus over twice daily administrated tacrolimus, Prograft®, is its
prolonged release and a higher bioavailability than other tacrolimus
formulations. Administration of LCP tacrolimus results in lower peaks, more
stable serum levels over 24 hours, and less fluctuation of blood concentrations
consequently. In different transplant populations, including lung transplant
patients, LCP tacrolimus has shown to be non-inferior when compared to IR
tacrolimus while using a lower dosage.

It might be hypothesized that LCP tacrolimus is as effective as IR tacrolimus
in lung transplantation patients, but results in less toxic side effects.
Lower peak levels of tacrolimus and thereby reducing incidence of renal
impairment, but without compromising the immunosuppressive effect, might be
feasible with LCP tacrolimus.

Primary Objective: to show a reduction in eGFR decline in patients treated with
LCP tacrolimus compared to IR tacrolimus. Secondary objectives will include
investigating the potential decline in other known side effects of calcineurin
inhibitors i.e. hypertension, new onset diabetes mellitus and neurotoxicity, in
patients treated with LCP tacrolimus compared to IR tacrolimus. Furthermore,
the efficacy in relation to transplant function, difference in quality of life
and pharmacogenetic properties for both formulas will be assessed.

Randomized open label phase 3 controlled trial

2 cohort will be formed:
- cohort 1: participants direct post transplantation who will randomized for
oral LCP tacrolimus or IR tacrolimus within 1 week after transplantation
- cohort 2: participants > 1 year after transplantation and clinically stable
and on stable dose of IR tacrolimus who will be randomized to LCP tacrolimus or
continue IR tacrolimus

LCP tacrolimus is the investigational drug, and will be compared to IR
tacrolimus which is standard therapy after lung transplantation.

Patients will receive all necessary care and treatments as per normal routine,
which entails regular blood, urine and pulmonary function tests. Participants
will be followed in the outpatient clinic every 3 months according to the
routine follow-up scheme in the University Medical Center Groningen (UMCG).
Laboratory data, lung function data, rejection data, blood pressure
measurements, data on rejection, infections, malignancies are collected form
clinical records or when adverse events are reported bij participants of
caregivers.

Solid organ transplant recipients in the University Medical Center Groningen
participate in TransplantLines, a large cohort and biobank study, with the aim
to improve graft and recipients outcome. Data from the biobank, blood samples,
questionnaires and assessment will be used to investigate our study endpoints.

study activities for the REVOLUTION participants entails being present at all
study visits where baseline data is collected, medication is checked, advers
events are checked.