Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00333593 |
| Other study ID # |
H2003/01440 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1/Phase 2
|
| First received |
June 5, 2006 |
| Last updated |
December 26, 2006 |
| Start date |
June 2006 |
| Est. completion date |
November 2006 |
Study information
| Verified date |
December 2006 |
| Source |
Austin Health |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Australia: Department of Health and Ageing Therapeutic Goods Administration |
| Study type |
Interventional
|
Clinical Trial Summary
Patients within the intensive care unit who have severe infections causing shock and kidney
failure have almost a 60% risk of dying despite antibiotic therapy, surgical drainage of the
site of infection and intensive care support with fluids, nutrition, mechanical ventilation
and continuous artificial kidney support. This persistently high death rate continues to
stimulate the development of new approaches to the treatment of septic shock.
Much clinical and molecular biology research suggests that these patients die because of an
uncontrolled immune system’s response to infection. This response involves the production of
several substances (so called “humoral mediators”), which enter the blood stream and affect
the patient's organs ability to function and the patient's ability to kill germs. These
substances may potentially be removed by new artificial filters similar to those currently
used during continuous hemofiltration (the type of artificial kidney support used in
intensive care).
Recent investigations by ourselves and others, however, have made the following findings:
1. Standard filters currently used in intensive care are ineffective in removing large
amounts of these “humoral mediators” because the holes in the filter are too small to
allow all of them to pass through
2. The standard filters currently used in intensive care are also ineffective in removing
large amounts of these “humoral mediators” because the standard filtration flow through
the membrane is less than 100 ml/min
3. When the filtration flow through the membrane is increased to above 100ml/min, patients
require a lesser dose of drugs to support their blood pressure which is an indirect
sign that the filters are clearing some of the "humoral mediators"
4. Even when the blood flow through standard filters is increased to above 100ml/min,
there is still not optimal clearing of "humoral mediators" It is possible, however,
that, using a different filter membrane with bigger holes in it, would make it easier
to clear the blood of these "humoral mediators". It is thought that this would be
noticeable clinically in the amount of drugs required to support blood pressure.
A filter that has these bigger holes is now available. It is made of the same material as
the standard filters that are currently used in the intensive care unit, only the holes have
been made bigger to allow these "humoral mediators" to be removed from the blood. This
polyamide filter is made of synthetic semipermeable material. This material is highly
compatible with human blood. This modified polyamide filter is made of exactly the same
compatible material but the holes in the material are slightly larger through a minor
modification of the manufacturing process.
This larger hole filter has now been used in preliminary studies in humans and has been
found to reduce the blood levels of some "humoral mediators". Laboratory studies conducted
by ourselves showed that this new filter can achieve the highest reported clearance of some
of the "humoral mediators" with minimal effect on useful proteins in blood such as albumin
during hemodialysis. This loss is very small and unlikely to contribute to any detectable
clinical changes.
We, therefore, now propose to study the effect of using new large hole filters with
hemodialysis in patients with severe infections and acute kidney failure.
We wish to compare the effect of this new therapy to that of standard filters. The new
therapy will be considered to be effective if it lowers the amount of drugs used to support
blood pressure and if it lowers the blood levels of some "humoral mediators" more than
standard therapy. We will also monitor blood levels of important components of blood such as
albumin and electrolytes in each group.
This is a pilot study involving only 10 patients who will each receive 4 hours of the
standard therapy and 4 hours of the new therapy. Which treatment the patient receives first
will be random (like the tossing of a coin). Blood samples will be taken at the start and
after 4 hours of each treatment. The waste product of dialysis called spent dialysate will
also be collected for the measurement of humoral mediators at the start and after 4 hours of
each treatment. The changes in blood pressure and drugs used to support it will be recorded
hourly. As patients involved in the study would normally receive hemofiltration because of
their kidney failure, all the risks and benefits associated with the procedure would be
unchanged. The only risk to patients would come from exposure to a modified membrane and
from having two additional spoonfuls of blood taken.
If this new membrane were found to have a major effect on the blood level of "humoral
mediators" and on the patients’ blood pressure, further studies would then be justified to
assess its clinical effects (time in ICU, time in hospital, time on ventilator, duration of
organ failure, etc).
Description:
BACKGROUND AND RATIONALE
The combination of acute renal failure (ARF) and sepsis is associated with a very high
morbidity and mortality (1). Accordingly, there have many attempts to develop better
treatments for this condition.
Much clinical and molecular biology research suggests that septic shock occurs because of
the uncontrolled immune system’s response to infection (2-13). This response involves the
production of several substances (so called “humoral mediators”), which enter the blood
stream and, at different times in the course of the patients’ illness, cause either severe
inflammation or profound depression of the immune system’s ability to kill microbes.
The vast majority of these substances (cytokines, complement anaphylatoxins, platelet
activating factor, leukotrienes, chemokines), which are responsible for this state of “blood
poisoning” are water soluble and of small to middle molecular weight (up to 40 kilodaltons).
These properties make them potentially removal by artificial membranes similar to those used
during continuous hemofiltration (the type of artificial kidney support used in intensive
care).
It is possible that using a different and more porous membrane, the removal of such
cytokines would be much more efficient and the clinical benefits of blood purification
would, therefore, be greater.
A membrane of this kind is now available. It is a modification (moderate increase in pore
size) of standard material called polyamide, which has already been used in millions of
people for dialysis and hemofiltration.
This larger pore polyamide membrane has now been used in preliminary studies in humans (14)
and has been found to be capable of lowering the blood levels of a marker cytokine
(interleukin-6, molecular weight: 26.2 kD).
In laboratory studies conducted by ourselves, this new polyamide membrane achieves the
highest reported cytokine and beta2-Microglobulin - as another marker of removal of middle
molecules - clearances in the literature and is associated with a negligible loss of albumin
(15).
Recent investigations by ourselves and others, however, have made the following findings:
1. Standard membranes are of only limited effectiveness in filtering these “humoral
mediators” (16)
2. Unless high volume plasma-water exchange is applied (100 ml/min), the effect of blood
purification on the blood levels of these mediators are minimal (17-20)
3. High volume hemofiltration with standard membranes, results in an improvement in the
state of the circulation such that the infusion of drugs used to support blood pressure
(noradrenaline) can be decreased (20).
4. Even with high volume hemofiltration the removal of “humoral mediators” such as
cytokines is still of limited efficiency (20)
It is possible that using a different and more porous membrane, the removal of such
cytokines would be much more efficient and the clinical benefits of blood purification
would, therefore, be greater.
A membrane of this kind is now available. It is a modification (moderate increase in pore
size) of standard material called polyamide, which has already been used in millions of
people for dialysis and hemofiltration.
We, therefore, propose to study the effect of combining hemodialysis and this new polyamide
membrane with larger pores in the treatment of patients with sepsis and acute kidney
failure. We wish to compare the effect of this new therapy to that of hemodialysis with a
standard membrane.
The terms of comparison (outcome measures) will be:
A). The effect of each therapy on the blood concentration of several cytokines (TNF-alpha,
IL-1 beta, Il-6, IL-8, and IL-10).
B). The effect of each therapy on the blood concentration of beta2-Microglobulin as another
marker of removal of middle molecules.
C). The effect of each therapy on blood pressure and the need for noradrenaline infusion
and, for safety assessment
D). The effect of each therapy on the blood concentration of albumin and electrolytes
If this new membrane were found to have a major effect on the blood concentration of
cytokines and on the patients’ blood pressure, further studies would then be justified to
assess its clinical effects (time in ICU, time in hospital, time on ventilator, duration of
organ failure, etc) in further trial.
STUDY OBJECTIVE
The aim of the study is to compare the effect of hemodialysis combined with a larger pore
membrane to that of hemodialysis with a standard membrane on
1. the serum concentration of several cytokines (efficacy assessment)
2. the serum concentration and clearance rates of beta2- Microglobulin (efficacy
assessment)
3. blood pressure and noradrenaline requirements (efficacy assessment)
4. the serum concentration of albumin and electrolytes (safety assessment)
NULL HYPOTHESIS
The use of hemodialysis combined with a larger pore membrane has no effect on serum
cytokine or beta2-Microglobulin levels, blood pressure and noradrenaline requirements
when compared to hemodialysis with a standard membrane.
STUDY DESIGN
This study is a phase I/II equivalent investigation. It is a pilot, randomised,
crossover, controlled study. Eligible patients will receive both treatments. However,
the order of treatment (first treatment A and then B or vice versa) will be allocated
in a random fashion (computer generated random numbers).
After completing the first treatment, patients will then be crossed over to the
alternative treatment.
Treatments will consist of either:
A) hemodialysis with a new polyamide (P2SH) membrane for 4 hours or B) hemodialysis
with a standard polyamide membrane
Blood will be sampled (serum cytokine and beta2-Microglobulin measurement) at the start
of each treatment and after 4 hours of each treatment. Dialysate will also be collected
for the measurement of cytokines and beta2-Microglobulin in order to calculate cytokine
and beta2-Microglobulin clearance.
The changes in blood pressure and noradrenaline dose will be recorded hourly as is
routine in Intensive Care. Patient treatment will otherwise continue according to
clinical needs and to standard ICU care.
It is important to note that patients involved in the study would normally receive
standard hemofiltration anyway because of their kidney failure, with all the risks and
benefits associated with the procedure (insertion of double lumen catheter,
extracorporeal circulation, anticoagulation).
As part of the study, however, they will also receive increased intensity of treatment,
4 hours of exposure to a modified membrane and some additional blood sampling (one
spoonful).
It is possible that the effect of the first therapy would cross over to the second. To
control for this crossover effect, statistical comparison will be undertaken according
to order of treatment as well as type of treatment, as recently published. (23)
STUDY POPULATION
All patients who fulfil the consensus criteria for sepsis (21) and recently proposed
criteria for severe ARF (1) are eligible for the study.
SPECIFIC EXCLUSIONS
- Patients under 18 years of age.
- Patients who are pregnant or breastfeeding
- Patients with a known allergy to polyamide
- Patients expected to die within 24 hours
- Patients in whom there are limitations on the intensity of therapy
ENROLMENT
Once patient eligibility is established informed consent will be sought from the next
of kin. If informed consent is obtained, the patient will be enrolled in the study. The
ICU research nurse will be responsible for enrolment and subsequent data collection.
STUDY PROTOCOL
Following enrolment and randomisation, the patient will be allocated to either
treatment A or B.
An extracorporeal circuit will be set up for dialysis with the Fresenius 2008 machine.
The only difference will be that, one filter which is being applied, will be a larger
pore polyamide filter. The other filter whic is being applied, will be a standard
polyamide filter.
Each treatment will be applied for 4 hours. After each treatment, the extracorporeal
circuit will be flushed with Hartmann’s solution and the membrane changed to the
alternative material (cross over).
For each treatment, the following technical settings will apply:
1. Blood flow at 200 ml/min
2. Dialysate flow at 300 ml/min
3. Anticoagulation of filter with prefilter heparin, if necessary (e.g. 1,000 IU/hr)
4. Bicarbonate-buffered dialysate
After the completion of the 2 periods of 4 hours of hemodialysis, patients will revert
to standard therapy (hemofiltration with AN 69 membrane at 2 L/hr of plasma water
exchange) and continue their normal treatment.
Randomisation and Concealment
The randomisation will be based on random numbers generated by computer. The allocation
to either treatment A or B as the first treatment will be placed in an opaque envelope
by an independent person.
Once consent is obtained, the envelope will be opened and treatment initiated. Filters
will be blinded and both will have identical appearance, outlining only "Filter A" or
"Filter B", respectively, on a label sticking to each filter.
For reasons of patient safety, filter monitoring for membrane clotting requires that
the filter be visualized at all times.
EXPECTED SIZE OF TREATMENT DIFFERENCE
This study is designed to detect a 30% decrease in IL-6 levels. From a previous very
similar investigation (19), we also assume a standard deviation equal in size to the
effect being tested for. Using non-parametric paired comparison statistics (Wilcoxon
ranked sign test), a sample of 10 patients would offer a > 80% power of detecting a 30%
difference at an alpha of 0.05 (22).
CLINICAL OUTCOMES AND DATA ANALYSIS
Primary analysis will be performed on the basis of intention to treat. Secondary
analysis will be performed on per protocol analysis. The primary outcome measure for
this study is the clearance and the change in IL-6 levels The secondary outcome is the
the clearance and change in the levels of other cytokines and beta2-Microglobulin.
The other secondary outcome is the change in noradrenaline dose required to maintain
baseline mean blood pressure (typically 70 mmHg)
Treatment groups will be analysed for differences in IL-6 levels after 4 hours of
treatment.
It is expected from clinical observation that the criteria for normal distribution will
be violated. Therefore comparison will be performed using a non-parametric test
(Wilcoxon ranked sign test). Statistical significance will be set at p<0.05.
The groups will also be tested for differences in secondary outcome variables. Such
secondary outcome variables are:
1. Absolute change in all serum cytokine levels for each cytokine and for
beta2-Microglobulin
2. Percentage change in noradrenaline dose
3. Change in blood pressure from pre-treatment value to value after 4 hours of
treatment
4. Percentage change in serum cytokine levels for each cytokine
Using the primary outcome variable, this study has an 80% power of detecting a 30%
difference at an alpha of <0.05.
It is expected from clinical observation that recruitment of 10 patients will take 3
months.
Data Collection
Data collection will be by the Intensive Care Dept. research nurse and research
fellows.
The following variables will be obtained:
Name, gender, age and medical record number
Date of admission to ICU
Admission diagnosis
SAPS II illness severity score on admission
Time of onset of septic shock
Time of onset of ARF
Time of onset of hemofiltration
Hemodynamic indices, temperature and biochemical indices at baseline and after 4 hours
Use of inotropic drugs and dose
Use of vasopressor drugs and dose
Hourly urine output (if present)
Time of onset of mechanical ventilation
Fluid balance during each 4 hours of treatment
Albumin and electrolytes at baseline and after 4 hours
CONCOMITANT MEDICATIONS
Concomitant medications will be administered according to standard intensive care
ADVERSE EVENTS
If any adverse events occur which may be related to the trial device, treatment will be
stopped. The event will be immediately reported to the Ethics Committee according to
institutional protocol.
PROTOCOL VIOLATIONS
All protocol violations will be recorded. It will then be decided whether the nature of
such violations has been such that the patient should be excluded from primary data
analysis.
WITHDRAWAL
The treating clinician will have the right to withdraw the patient from the study if he
or she believes that continued participation is jeopardizing the patient’s well being.
Patients who require take back to theatre during the study period for a surgical
emergency will be withdrawn from the trial.
CONSENT TO TRIAL ENROLMENT
In all patients it may be necessary to ask for consent from the next of kin. All of
these patients are mechanically ventilated and too ill to give informed consent
ETHICAL ISSUES
The polyamide material used for the study membrane is very safe and has been used in
millions of patients. Its modification is exclusively to the pore size, not to its
composition. The effect of pore size on protein losses appears minimal for proteins >
60 kD in molecular weight such as albumin. Accurate in vitro testing confirms this.
Preliminary phase I data also confirms such safety. We consider the potential benefit
of this intervention theoretically significant.
Given the balance of benefits and risks, we consider it ethical to proceed and seek
informed consent.
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