Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01416753 |
| Other study ID # |
EK.-Nr. 365/2011 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
August 12, 2011 |
| Last updated |
August 30, 2012 |
| Start date |
September 2011 |
| Est. completion date |
August 2012 |
Study information
| Verified date |
August 2012 |
| Source |
Medical University of Vienna |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Agency for Health and Food Safety: Austria |
| Study type |
Interventional
|
Clinical Trial Summary
Background: Data generated with the body composition monitor (BCM, Fresenius) show based on
bioimpedance technology, that chronic fluid overload in hemodialysis patients is associated
with poor survival. However, removing excess fluid by lowering dry weight can be accompanied
by intradialytic and postdialytic complications. Here, we aim at testing the hypothesis
that, in comparison to conventional hemodialysis, blood-volume monitored regulation of
ultrafiltration and dialysate conductivity (UCR) and/or regulation of ultrafiltration and
temperature (UTR) will decrease complications when ultrafiltration volumes are
systematically increased in fluid overloaded hemodialysis patients.
Methods/Design: BCM-measurements yield results on fluid overload (in liters), relative to
extracellular water (ECW). In this prospective, multicenter, triple-arm, parallel group,
cross-over, randomized, controlled clinical trial, we use BCM-measurements, routinely
introduced in our 3 maintenance hemodialysis centers shortly prior to the start of the
study, to recruit 60 hemodialysis patients with fluid overload (defined as ≥15% ECW).
Patients are randomized 1:1:1 into UCR, UTR and conventional hemodialysis groups.
BCM-determined, 'final' dry weight is set as -7% ECW postdialysis, and reached by reducing
the previous dry weight, in steps of 0.1 kg per 10 kg body weight, during 12 hemodialysis
sessions (one study phase). In case of intradialytic complications, dry weight reduction is
decreased, according to a pre-specified algorithm. A comparison of intra- and postdialytic
complications among study groups constitutes the primary endpoint. In addition, we will
assess relative weight reduction, changes in residual renal function, quality of life
measures, and predialysis levels of various laboratory parameters including C-reactive
protein, troponin T, and N-terminal pro-B-type natriuretic peptide, before and after the
first study phase (secondary outcome parameters).
Discussion: Patients are not requested to revert to their initial degree of fluid overload
after each study phase, Therefore, the cross-over design of the present study merely serves
the purpose of secondary end-point evaluation, for example to determine patient choice of
treatment modality. Previous studies on blood volume monitoring have yielded inconsistent
results. Since we include only patients with BCM-determined fluid overload, we expect a
benefit for all study participants, due to strict fluid management which decreases the
mortality risk of hemodialysis patients.
Description:
Hypothesis In comparison to conventional hemodialysis, regulation of ultrafiltration and
dialysate conductivity (UCR) and/or regulation of ultrafiltration and temperature (UTR) will
decrease intra- and postdialytic complications when ultrafiltration volumes are
systematically increased in fluid overloaded hemodialysis patients.
Objectives and Outcome Measures The primary objective is to demonstrate superiority of
ultrafiltration and dialysate conductivity regulation (UCR) and/or ultrafiltration and
temperature regulation (UTR) over conventional hemodialysis, in preventing intra- and
postdialytic complications, when fluid overloaded hemodialysis patients receive systematic
fluid reduction, to reach a final dry weight of 7% ECW postdialysis. The primary outcome
measure is the total number of hemodialysis sessions per patient that were accompanied,
intra- or postdialytically, by at least one symptom most likely related to fluid withdrawal
(as specified in Table 1), divided by the number of hemodialysis sessions at risk (as by
study protocol: 12 sessions per patient in study phase 1). Both groups, UCR and UTR, will be
compared against the conventional hemodialysis group, and afterwards against one another,
using the two-sided Student's t-test.
The secondary objectives are:
1. To demonstrate superiority of ultrafiltration and dialysate conductivity regulation
(UCR) and/or ultrafiltration and temperature regulation (UTR) over conventional
hemodialysis, in preventing specific intradialytic complications:
1. intradialytic cramping
2. clinically asymptomatic, intradialytic hypotension (>40 mmHg drop in systolic
blood pressure within 30 minutes)
3. clinically symptomatic, intradialytic hypotension (>40 mmHg drop in systolic blood
pressure within 30 minutes)
4. clinically symptomatic, intradialytic hypotension (even if it is not possible to
identify a sudden drop in blood pressure, e.g. patients may slowly move towards
low blood pressure values [f. ex. below 100 mmHg systolic blood pressure], and
report symptoms)
5. unspecified intradialytic symptoms or events, which are most likely related to
fluid withdrawal
6. patient-reported postdialysis complication, most likely related to fluid
withdrawal
when fluid overloaded hemodialysis patients receive systematic fluid reduction, to
reach a final dry weight of -7% ECW postdialysis. The secondary outcome measure for
objective [a] is the total number of hemodialysis sessions per patient which were
accompanied by the respective symptom most likely related to fluid withdrawal (1 to 6),
divided by the number of hemodialysis sessions at risk (as by study protocol: 12
sessions per patient in study phase 1). Both groups, UCR and UTR, will be compared
against the conventional hemodialysis group, and afterwards against one another, using
the two-sided Student's t-test.
2. To demonstrate superiority of UCR and/or UTR over conventional hemodialysis in allowing
patients to reach a lower body weight, relative to his/her postdialysis weight at the
beginning of study phase 1 (time zero). The secondary outcome measure for objective [b]
is the difference in postdialysis body weight from time zero to the end of study phase
1, divided by the postdialysis body weight at time zero.
Example: If a patient has a postdialysis body weight of 65 kg at time zero (the last
hemodialysis session before the first dry weight reduction), and reaches a postdialysis
body weight of 62 kg at the end of the first study phase, his difference in body weight
will be 65 kg - 62 kg =3 kg. Relative to this patient's postdialysis body weight at
time zero, weight reduction from beginning to end of study phase 1 will be
3/65*100=4.61%.
The relative weight reduction in both groups, UCR and UTR, will be compared against the
conventional hemodialysis group, and afterwards against one another, using the
two-sided Student's t-test.
3. To assess if stricter volume control in fluid overloaded patients (using UCR, UTR or
conventional hemodialysis) diminishes residual renal function. The secondary outcome
measure for objective [c] is the difference in 24h urine volume from time zero to the
end of study phase 1, divided by the urine volume at time zero. The relative urine
reduction in both groups, UCR and UTR, will be compared against the conventional
hemodialysis group, and afterwards against one another, using the two-sided Student's
t-test.
4. To assess the amount of sodium transferred to the patient or withdrawn from the patient
during conventional hemodialysis, UCR and UTR.
The amount of sodium removed during hemodialysis is a function of the ultrafiltration
volume, the effective diffusion gradient for sodium, and diffusive sodium clearance.
The effective diffusion gradient depends on the plasma water - dialysate sodium (DNa)
difference, and the Gibbs-Donnan coefficient, the latter being a function of the plasma
protein concentration but also being influenced by other ions in the dialysate. The
assumption that sodium removal by ultrafiltration is equal to the plasma water sodium
concentration, multiplied by the ultrafiltration volume, is a simplification.
Electrolyte balances may also be influenced by the membrane charge. Therefore, the
amount of sodium transferred will be measured on the dialysate side. Sodium transfer
will be calculated from the difference between the mean sodium concentration in
partially collected, used dialysate and the fresh DNa concentration, multiplied by the
total amount of dialysate used. Results will be compared to a two pool sodium model and
parameters of the model will be adjusted using the measured transfer data.
The above described method is not applicable to the UCR group because the sodium
concentration of fresh dialysate is not kept constant during treatment. In order to
establish the model, we will measure at least 10 patients during 3 hemodialysis
sessions, and due to the formerly stated, we can only use the dialysate from patients
in the conventional hemodialysis group and in the UTR group.
However, after having established this model, sodium transfer for all patients -
conventional, UTR, and UCR - can be calculated using this very model.
The amount of sodium transferred to or withdrawn from the patient will be calculated
for each patient, according to the model established in the way stated here above. The
secondary outcome measure for objective [d], e.g. the sodium transferred in both
groups, UCR and UTR, will be compared against the conventional hemodialysis group, and
afterwards against one another, using the two-sided Student's t-test.
5. To assess if stricter volume control by conventional hemodialysis, UCR and/or UTR
influences predialysis serum concentrations of (1) C-reactive protein, (2) D-dimer, (3)
fibrinogen, (4) troponin T, (5) N-terminal pro-B-type natriuretic peptide. These
proteins are used as read-outs for inflammation (1, 2, 3), coagulation (2, 3), and
cardiac function (4, 5) and are routinely determined at all three participating
centers. The secondary outcome measure for objective [e], e.g. the concentrations of
the indicated laboratory parameters in both groups, UCR and UTR, at time zero and at
the end of study phase 1, will be compared against the conventional hemodialysis group,
and afterwards against one another, using the two-sided Student's t-test. The
individual change in these parameters, from time zero to the end of study phase 1, will
be compared likewise.
6. To assess if stricter volume control in fluid overloaded patients (using UCR, UTR or
conventional hemodialysis) affects the concentration of various proteins that might
serve as novel biomarkers (including high density lipoprotein [HDL]-associated
surfactant protein B, HDL-associated serum amyloid A, HDL-associated apoC-II, plasma
tryptophan, plasma choline, plasma trimethylanine-N-oxide; plasma endotoxin).
We have recently discovered that various proteins, including those mentioned here
above, may render HDL dysfunctional, in hemodialysis patients. Especially with
surfactant, we suspect an association with fluid overload. Moreover, plasma tryptophan,
plasma choline, and plasma trimethylanine-N-oxide are markers of end stage renal
disease. Since one or several of these proteins or molecules might serve as novel
biomarkers, we would like to use the context of the present trial to establish
diagnostic assays and analyze potential changes in the serum concentration of these
proteins, before and after fluid removal.
Endotoxin, found in the cell membranes of gram-negative bacteria, is a biomarker
representing the gut flora. Endotoxin has been shown to be associated with
inflammation, nutritional status and even mortality in hemodialysis patients. An
incremental rise in endotoxin levels has been shown along with the progression of
chronic kidney disease, and especially initiation of hemodialysis. It has been
suggested that hemodialysis patients might have high endotoxin levels in the blood due
to repeated bacterial translocation from the gut during hemodialysis, secondary to
intradialytic changes in blood pressure and/or tissue perfusion. An association with
chronic fluid overload has not yet been established, but might be suspected, as a
consequence of higher ultrafiltration rates and thus decreased intradialytic stability.
Here we will measure endotoxin levels with an amebocyte limulus assay in all study
patients, at time zero and at the end of study phase 1.
The secondary outcome measure for objective [f], for example HDL-associated serum
amyloid A in both groups, UCR and UTR, at time zero and at the end of study phase 1,
will be compared against the conventional hemodialysis group, and afterwards against
one another, using the two-sided Student's t-test. The individual change in these
parameters, from time zero to the end of study phase 1, will be compared likewise. The
results of this secondary endpoint analysis will be published separately from the
clinical results of the present study.
7. To assess if stricter volume control in fluid overloaded patients (using UCR, UTR or
conventional hemodialysis) affects quality of life measures. The secondary outcome
measures for objective [g] are the mental component summary (MCS) and physical
component summary (PCS) derived from the Kidney Disease Quality of Life Short Form
(KDQoL-SFTM). The scale of both summary scores is 0-100 (higher indicating better
quality of life). MCS and PCS in both groups, UCR and UTR, at time zero and at the end
of study phase 1, will be compared against the conventional hemodialysis group, and
afterwards against one another, using the two-sided Student's t-test. The individual
change in these parameters, from time zero to the end of study phase 1, will be
compared likewise.
8. To demonstrate superiority of UCR and/or UTR over conventional hemodialysis in reducing
dialysis complications when previously fluid overloaded patients are entering phase 2
and phase 3 of the presented study. In study phases 2 and 3, patients either have to
reduce their dry weight further, or else have to maintain their newly reached dry
weight. The secondary outcome measures for objective [h] are potentially all of the
items described here above, and will be compared against the conventional hemodialysis
group, and afterwards against one another, in the same fashion as described here above.
9. To assess which hemodialysis treatment modality will be chosen by the patients at the
end of the study. The choice of treatment will be compared as follows: (1) number of
patients choosing UCR-treatment against number of patients choosing conventional
treatment; (2) number of patients choosing UTR-treatment against number of patients
choosing conventional treatment; (3) number of patients choosing UCR-treatment against
number of patients choosing UTR-treatment. The statistical test for analyses (1), (2)
and (3) will be the two-sided chi square test, for each analysis.
Superiority definition For all objectives listed, superiority will be assumed if a
statistically significant difference between one group versus another group can be
determined. With regards to the primary endpoint, according to our sample size calculation
(see below), this study is suited to detect a minimal difference of 10% between groups.
