Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00008826

Trial Description

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Title

Lung Water By Ultra-Sound Guided Treatment To Prevent Death and Cardiovascular Complications in High Risk End Stage Renal Disease Patients With Cardiomyopathy (Lust Study)

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Trial Acronym

LUST

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URL of the Trial

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Brief Summary in Lay Language

Volume overload is a leading risk factor for death and cardiovascular events in end stage
renal disease patients maintained on chronic dialysis, particularly in those with myocardial
ischemia and heart failure which represent a substantial fraction of this population. Early
identification of volume overload may prevent cardiovascular sequel in these patients but
clinical signs of volume expansion are unsatisfactory to reliably identify patients at risk
and to monitor them over time. On the other hand, however reliable, standard techniques for
measuring extracellular or circulating (blood) volume do not convey information on
fundamental heart function parameters that determine the individual haemodynamic tolerance
to volume excess and the response to ultrafiltration, i.e. left ventricular (LV) filling
pressure and LV function.

Extra-vascular lung water is critically dependent on these parameters and represents a proxy
of both, circulating volume and LV filling pressure and function, and may therefore be a
better criterion to identify patients at a higher risk of volume-dependent adverse clinical
outcomes and to monitor the effect of therapy aimed at preventing these outcomes. A fast (<
5 min.), easy to learn, simple and non-expensive technique which measures extra-vascular
lung water by using standard ultrasound (US) machines has been validated in dialysis
patients. Whether systematic measurement of lung water by this technique may translate into
better clinical outcomes in End Stage Renal Disease (ESRD) patients has never been tested.

The aim of this randomized clinical trial is that of testing a treatment policy guided by
extra-vascular lung water measurements by ultrasound to prevent death, decompensated heart
failure and myocardial infarction as well as progression of Left Ventricular Hypertrophy
(LVH) and LV dysfunction and hospitalization in high risk dialysis patients with myocardial
ischemia (a history of myocardial infarction with or without ST elevation or unstable
angina, acute coronary syndrome documented by ECG recordings and cardiac troponins or stable
angina pectoris with documented coronary artery disease by prior coronary angiography or
ECG) or overt heart failure (NYHA class III-IV).

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Brief Summary in Scientific Language

Randomization procedure: After enrollment, patients will be randomized in 2 groups:
treatment and control. The randomization will be performed by centre, with a 1:1 allocation
ratio, and it will be communicated by the coordinating centre in Reggio Calabria. An
allocation concealment will be observed.

Warning: based on the principle "once randomized, always randomized", if a patient drops out
the study he cannot simply be replaced by a new one. New patients must be randomized as
well.

Validation of core lab data: The core data to be collected in the LUST project/subprojects
should be validated by the following validation centres:

- CORE LUST STUDY DATA Echocardiographic data and US-lung data: Dr. Rosa Sicari and Dr.
Luna Gargani, CNR Institute of Clinical Physiology of Pisa, Italy (rosas@ifc.cnr.it).

- ANCILLARY LUST PROJECTS Pulse Wave Velocity data (PWV): Prof. Gerard London, Service
d'Hémodialyse, Hôpital F.H. Manhès, Fleury-Mérogis, France (glondon@club-internet.fr).

24 Ambulatory Blood Pressure Monitoring (ABPM) data: Dr. Grzegorz Bilo, Istituto
Auxologico Italiano of Milan, Italy (g.bilo@auxologico.it).

Preliminary training on US-B lines measurement is a pre-requisite for Nephrologists and
Cardiologists of each participating centre. After training (Skype meeting) an online
certification will be released to certify the level of expertise about US-B lines
measurements of all LUST study nephrologists and cardiologists.

Each participant centre will upload pertinent studies (echocardiography, 24h ABPM and PWV
data) into the LUST website and will timely receive a feedback by the validation centres,
whenever needed.

US Lung Scan technique A standard (3.0-MHz) echocardiography probe can be used for this
purpose. Examinations should be performed in the supine position. To detect lung water, both
sides of the chest should be scanned both in the anterior and lateral part from the second
to the fourth (on the right side to the fifth) intercostals spaces, at parasternal, mid
clavea, anterio-axillar and mid-axillary lines, as previously described (Am J Cardiol
2004;93:1265-70). An US-B line is a hyperechoic, coherent US bundle at narrow basis going
from the pleura to the limit of the screen. These extended lines (also called comets) arise
from the pleural line and should be differentiated from short comets' artifacts that may
exist in other regions. US-B lines starting from the pleural line can be either localized or
scattered to the whole lung and be present either as isolated US-B lines or in groups
(with a distance >7 mm between 2 extended comets). The sum of US-B lines produces a score
reflecting the extent of LW accumulation. If you do not detect any US-B line, the score is
0.

The investigators warn you about fixed US-B lines, due not to lung water but to fibrosis or
inflammatory processes. These comets should be registered but not counted as US-B lines. The
cause that underlies these artefacts should be described.

In patients allocated to the active arm of the study, any decision about weight
reduction will be taken by Nephrologists only on the basis of pre-dialysis US-scans.
However, also post-dialysis US-B lines measurement must be performed and registered. In the
active and in the control arm as well, US-scans will be performed by the local
cardiologist in coincidence with the echocardiographic study. It is crucial for the purpose
of this study that cardiologists keep nephrologists involved in the LUST study blinded with
respect to the number of US-B lines of patients of the control group.

Timing

- In patients allocated to the control and the active arms, US-B lines should be
performed at baseline and at 6, 12 and 24 months by the local cardiologist, in a
non-dialysis day either on a Thursday or on a Friday, depending on the dialysis
schedule.

- In patients allocated in the treatment arm, the application of US-B scans should be
performed as follows:

- In patients with less than 15 US-B lines, ultrafiltration (UF) will not be modified
and the US-B lines monitoring will be performed by the nephrologist at monthly
intervals;

- In patients with more than 15 US-B lines (either at baseline or at any of the
monthly US-B Lung scans) UF will be performed by scheduling longer and/or additional
dialyses (see below). In these patients, monitoring of US pre-dialysis and
post-dialysis -B lines will be repeated at least once a week, until the goal is
achieved (see next section).

- Furthermore, in patients in the active arm, pre- and post-dialysis US-lung scans can
be repeated at discretion of the nephrologist, i.e. whenever he/she believes that it
can be useful applying this technique for monitoring the volume status of the
patient, for example in a patient with <15 US-B lines who subsequently manifests a
rise in body weight or in a patient who develops hypotension or frank hypotensive
episodes during dialysis .

In brief, in the treatment group, monitoring is scheduled once a week (before and after
dialysis), or even more frequently if the nephrologist believes that a more frequent
monitoring may be useful to track the desired UF goal. When the number of US-B lines
falls below 15, the measurements will be repeated at monthly intervals.

Weight reduction in patients with more than 15 US-B lines

In patients randomized to the treatment arm and with a number of US-B lines >15, a decrease
of dry weight is required to reduce lung water, according to the following scheme derived by
a pilot study at the coordinating centre and at the Iasi Nephrology Unit:

- 15-30 US-B lines: decrease dry weight by 300 g over the following week (about 100 g
per session)

- 31-40 US-B lines: decrease dry weight by 450 g over the following week (about 150 g
per session)

- > 40 US-B lines: decrease dry weight by 600 g over next week (about 200 g per session).

Attempts to lower dry weight according to the previous scheme should continue until the
US-B lines goal (<15) is attained. If the patient does not tolerate attempts to decrease
dry weight for 2 weeks (i.e. if he/she develops hypotension, cramps and other symptoms)
extra haemodialysis sessions should be considered.

If the goal (<15 pre-dialysis US B-lines) is not achieved after 4-6 weeks, or in case the
patient does not tolerate UF, drug treatment (carvedilol, ACEi, ARB) intensification or
introduction should be considered.

Once the goal is achieved, it is recommended to confirm it by repeating the measurement of
US-B lines at least once, for example before the following dialysis.

Warnings:

- In patients in the active arm with initial pre-dialysis US-B lines <15 and in those
who achieve this goal thanks to body fluids subtraction who develop cramps
and/or symptoms of extracellular volume depletion (low dry weight) the decision of
increasing dry weight should be accompanied by close US-B lines monitoring (i.e. every
dialysis session until the patient stabilizes).

- In patients with >15 pre-dialysis US-B lines who do not tolerate dry weight decrease
due to hypotension and who are on hypotensive/cardioprotective drugs treatment
(carvedilol/ACEi) the dose of these drugs should be down-titrated and stopped, if
needed. These drugs in these patients should be always given after dialysis (before
going to bed, at night) rather than pre-dialysis.

Clinical (pre-dialysis) evaluation of volume status In both groups (treatment and control
group), a standard pre-dialysis clinical evaluation of volume status should be done, as
it is recommended in good clinical practice. This evaluation should consider blood
pressure and change of blood pressure over time, pedal edema, presence/absence of dyspnea,
crackles on lung auscultation (see below), body weight gain inter-dialysis and body
weight trajectory over time. In the active arm of the study these data should also be
formally registered whenever US-B lines measurements are done. In the control group,
evaluation of volume status needs to be formally registered only in coincidence of
the echocardiographic studies.

The following scale will be used for the evaluation of Crackles :

1. No crackles

2. I am uncertain about the presence of fine crackles

3. Definite fine crackles at lung bases

4. Moderate crackles

5. Bilateral, diffuse crackles

For clinical edema, the following scale will be used:

1. No clinical edema

2. Slight pitting (2 mm depth) with no visible distortion

3. Somewhat deeper pit (4 mm) with no readily detectable distortion

4. Noticeably deep pit (6 mm) with the dependent extremity full and swollen

5. Very deep pit (8 mm) with the dependent extremity grossly distorted

Echocardiographic measurements In both the intervention and control arm, cardiologists
involved in the LUST study will perform the echocardiographic measurements at baseline, 6,
12 and 24 months, in a non-dialysis day on a Thursday or on a Friday, depending on the
dialysis schedule. These echocardiogram are "research echocardiograms". For this reason, it
is fundamental to keep nephrologists blind about the results of these echocardiographic
readings.

Nevertheless, nephrologists are allowed to consult a cardiologist (be him the LUST
cardiologist or another one) for a "clinical echocardiogram" if and when clinical problems
arise which demand the application of echocardiographic studies for diagnostic
reasons or for monitoring any underlying cardiac problem.

Detailed information about standardization of echocardiographic study has been prepared by
echocardiography validation laboratory (Dr. Rosa Sicari and Dr. Luna Gargani, IFC CNR,
Pisa).

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Organizational Data

  •   DRKS00008826
  •   2015/08/12
  •   2014/10/28
  •   yes
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Secondary IDs

  •   NCT02310061  (ClinicalTrials.gov)
  •   ERA-EDTA-01062012  (Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy)
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Health Condition or Problem studied

  •   Kidney Failure, Chronic
  •   N18 -  Chronic kidney disease
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Interventions/Observational Groups

  •   Procedure: Extra-vascular lung water measurements by ultrasound (LW-US)
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Placebo
  •   Treatment
  •   Parallel
  •   III
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Primary Outcome

- Cumulative incidence of the composite outcome "death, myocardial infarction, heart failure".; time frame: All events occurred during 24 months of follow up will be assessed at 1 year and 2 years after the start of the study. For Time-to-Event analyses, we will consider the time from the first visit to the first occurrence of death, or MI or heart failure.; Myocardial infarction and heart failure will be defined on the basis of international standard protocols.
- The following figures we expect to occur in the two study arms:
Active arm: 30% Control arm: 45%
- All-cause and cardiovascular hospitalization.; time frame: All events occurred during 24 months of follow up will be assessed at 1 year and 2 years after the start of the study. For Time-to-Event analyses, we will consider the time from the first visit to the first occurrence of all-cause and CV hospitalization; Hospitalization will be characterized on the basis of ICD9 codes.
- The following figures we expect to occur in the two study arms:
Active arm: 1.00 hospitalization/patientyear Control arm: 1.50 hospitalization/patientyear
- Left atrial volume; time frame: Left atrial volume (LAV) will be measured by cardiologists at baseline, 6, 12 and 24 months; Left atrial volume will be measured by Echocardiography.
We expect the following changes in LAV between the two study arms:
Active arm: -2±17 Control arm: 4±17
- Diastolic function.; time frame: Diastolic function (E/E') will be measured by cardiologists at baseline, 6, 12 and 24 months; Diastolic function will be assessed by Echocardiography.
We expect the following changes in E/E' between the two study arms:
Active arm: -2±6 Control arm: 0±6
- Left ventricular mass index (LVMI); time frame: LVMI will be measured by cardiologists at baseline, 6, 12 and 24 months; LVMI will be measured by Echocardiography.
We expect the following changes in LVMI between the two study arms:
Active arm: - 2±11 Control arm: 3±11
- Left ventricular ejection fraction (LVEF); time frame: LVEF will be measured by cardiologists at baseline, 6, 12 and 24 months; Left ventricular ejection fraction will be measured by Echocardiography.
We expect the following changes in LVEF between the two study arms:
Active arm: 3±9% Control arm: 0±9%

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Secondary Outcome

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Countries of Recruitment

  •   France
  •   Germany
  •   Greece
  •   Israel
  •   Italy
  •   Poland
  •   Romania
  •   Slovenia
  •   Spain
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Locations of Recruitment

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Recruitment

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  •   2013/11/30
  •   500
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- Age > 18 years

- Dialysis vintage > 3 months

- A history of myocardial infarction with or without ST elevation or unstable angina,
acute coronary syndrome, documented by ECG recordings and cardiac troponins, or
stable angina pectoris with documented coronary artery disease by prior coronary
angiography or ECG or dyspnoea class III-IV NYHA

- Written consent to take part in the study

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Exclusion Criteria

- Cancer or other advanced non cardiac disease or comorbidity (e.g. end-stage liver
failure) imposing a very poor short-term prognosis

- Active infections or relevant inter-current disease

- Inadequate lung scanning and echocardiographic studies

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Addresses

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    • Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy
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    • Manhes Hospital, Fleury Mérogis, France
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    • Saarland University
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    • Centre Hospitalier Universitaire, Amiens
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    • Renal Unit, University of Madrid
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    • Universitatea de Medicina si Farmacie Iasi
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    • Medical University of Silesia
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    • Hospital Universitari de Bellvitge
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    • Akdeniz University
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    • King's College London
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    • CNR-IBIM and Nephrology Unit, Reggio Calabria
    • Carmine Zoccali, Prof 
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    • Carmine Zoccali, Prof 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

  •   Kramer A, Stel V, Zoccali C, Heaf J, Ansell D, Grönhagen-Riska C, Leivestad T, Simpson K, Pálsson R, Postorino M, Jager K; ERA-EDTA Registry. An update on renal replacement therapy in Europe: ERA-EDTA Registry data from 1997 to 2006. Nephrol Dial Transplant. 2009 Dec;24(12):3557-66. doi: 10.1093/ndt/gfp519. Epub 2009 Oct 9.; 19820003
  •   Charra B, Calemard E, Ruffet M, Chazot C, Terrat JC, Vanel T, Laurent G. Survival as an index of adequacy of dialysis. Kidney Int. 1992 May;41(5):1286-91.; 1614043
  •   Sinha AD, Agarwal R. Can chronic volume overload be recognized and prevented in hemodialysis patients? The pitfalls of the clinical examination in assessing volume status. Semin Dial. 2009 Sep-Oct;22(5):480-2. doi: 10.1111/j.1525-139X.2009.00641.x. Epub 2009 Sep 9.; 19744155
  •   Staub NC. Pulmonary edema. Physiol Rev. 1974 Jul;54(3):678-811. Review.; 4601625
  •   Crandall ED, Staub NC, Goldberg HS, Effros RM. Recent developments in pulmonary edema. Ann Intern Med. 1983 Dec;99(6):808-22. Review.; 6360001
  •   Jambrik Z, Monti S, Coppola V, Agricola E, Mottola G, Miniati M, Picano E. Usefulness of ultrasound lung comets as a nonradiologic sign of extravascular lung water. Am J Cardiol. 2004 May 15;93(10):1265-70.; 15135701
  •   Picano E, Gargani L, Gheorghiade M. Why, when, and how to assess pulmonary congestion in heart failure: pathophysiological, clinical, and methodological implications. Heart Fail Rev. 2010 Jan;15(1):63-72. doi: 10.1007/s10741-009-9148-8. Review.; 19504345
  •   Picano E, Frassi F, Agricola E, Gligorova S, Gargani L, Mottola G. Ultrasound lung comets: a clinically useful sign of extravascular lung water. J Am Soc Echocardiogr. 2006 Mar;19(3):356-63. Review.; 16500505
  •   Agricola E, Bove T, Oppizzi M, Marino G, Zangrillo A, Margonato A, Picano E. "Ultrasound comet-tail images": a marker of pulmonary edema: a comparative study with wedge pressure and extravascular lung water. Chest. 2005 May;127(5):1690-5.; 15888847
  •   Mallamaci F, Benedetto FA, Tripepi R, Rastelli S, Castellino P, Tripepi G, Picano E, Zoccali C. Detection of pulmonary congestion by chest ultrasound in dialysis patients. JACC Cardiovasc Imaging. 2010 Jun;3(6):586-94. doi: 10.1016/j.jcmg.2010.02.005.; 20541714
  •   Cice G, Ferrara L, Di Benedetto A, Russo PE, Marinelli G, Pavese F, Iacono A. Dilated cardiomyopathy in dialysis patients--beneficial effects of carvedilol: a double-blind, placebo-controlled trial. J Am Coll Cardiol. 2001 Feb;37(2):407-11.; 11216954
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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   2
  •   2015/06/17
* This entry means the parameter is not applicable or has not been set.