To investigate non-inferiority regarding the safety of a 6% HES solution (Volulyte 6%) versus an electrolyte solution (Ionolyte) in patients undergoing elective abdominal surgery.
ID
Source
Brief title
Condition
- Electrolyte and fluid balance conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Difference in mean estimated glomerular filtration rate (eGFR) (calculated from
highest cystatin-C levels measured duringpostoperative days 1-3 (POD 1-3))
between the two treatment groups. This difference will be calculated for the
change from the pre-operative
baseline value.
Secondary outcome
Safety:
* Renal function
o Cystatin-C
o Serum creatinine (SCr)
o Cystatin-C-based estimated glomerular filtration rate (eGFR)
o Cystatin-C-based mean eGFR (calculated from the highest cystatin-C level
during day 1-10, or hospital discharge whatever occurs first)
o SCr-based eGFR
o AKIN & RIFLE score (calculated)
o Urine output (if available)
* Coagulation
o Platelet count
o International norm ratio
o Activated partial thromboplastin time
* Inflammation
o C-reactive protein
* Adverse events
o (Serious) adverse events / reactions
* Calculated red blood cell loss
* Estimated intra-operative blood loss.
Outcome
o Composite of mortality and major post-operative
complications (including renal) until day 90
o Length of stay (LOS) in the hospital
o LOS in the intensive care unit (ICU) (if applicable)
o Fit for discharge from ICU/hospital
o Hours on mechanical ventilation
o In-hospital / out of hospital mortality (incl. cause)
o (New) renal replacement therapy (RRT).
Efficacy:
* Fluid administration
o Administration of IP volume
* Fluid balance
o Fluid input and output
* Haemodynamics/ vital signs
o Heart rate
o Temperature
o Mean arterial pressure
o Systolic arterial blood pressure
o Diastolic arterial blood pressure
o Central venous pressure (if available)
at least one of the following parameters to evaluate volume responsiveness and
guide IP administration within the volume algorithm:
o Stroke volume
o Stroke volume variation
o Stroke volume index
Pulse pressure variation
o Mean arterial blood pressure
* Laboratory data
o Arterial (preferred) blood gas analysis
- Partial pressure of carbon dioxide (pCO2)
- Partial pressure of oxygen (pO2)
- Bicarbonate (HCO3-)
- Arterial oxygen saturation (SaO2)
- Haemoglobin
- Haematocrit
- pH
- Base Excess
- Lactate
o Central venous oxygen saturation (ScvO2) (if available)
o Serum electrolytes
- Natrium (Na+)
- Potassium (K+)
- Calcium (Ca2+)
- Chloride (Cl-)
* Major post-operative complications (including renal).
Other variables:
* Demographic data & medical history
o Age
o Gender
o Height
o Weight
o Ethnicity
o Concomitant diseases & anamnestic baseline characteristics reflecting the
surgical risk
o Fluid input (colloids, crystalloids) in the 24 h prior to IP treatment start
Surgery related data
o Main diagnosis leading to surgery
o Type of surgery
o Skin incision / suture
* Concomitant medication
o Antibiotic therapy
o Contrast agents
o Diuretics
o Vasoactive/ inotropic drugs
o Blood products
o Basal infusion administration
o Crystalloid solutions / albumin
Background summary
The purpose of plasma volume substitutes is to compensate for a decrease in
intravascular volume, for example to counter during the surgery or after a
trauma, and hypovolemia, whereby the hemodynamics and the patient's vital
functions remain intact. Plasma volume substitutes are electrolyte solutions or
colloidal solutions. Both infusion solutions compensate for the loss of blood.
Electrolyte solutions containing various salts (electrolytes) which are
dissolved in water. They are administered in the vein, but move partially into
the surrounding tissue, where they may give rise to tissue swelling (edema).
However, colloid solutions comprise an additional active substance, such as
HES, whereby the administered liquid is held in the blood vessels. Therefore,
it is assumed that in the use of colloid solutions need to be administered less
infusion fluid in order to compensate for the loss of blood and thus there is
less formation of harmful tissue swelling. There is evidence that solutions
containing HES have a positive effect on the stabilization of the blood
circulation and tissue perfusion in surgical patients.
This clinical trial was imposed by the European Medicines Agency to reassess
any side effects of HES solutions in surgical patients. For this purpose this
clinical study, two different plasma volume substitutes are compared with
respect to safety and efficacy: a HES solution (the research test product
"Volulyte 6%") and an electrolyte solution (the research reference product
"Ionolyte").
HES solutions and electrolyte solutions have been legally approved for years
and have been used routinely during operations for decades. In January 2018,
the European Medicines Agency EMA found that in clinical routine, HES solutions
were often used outside the allowed (approved) indications and as a result
recommended to suspend (i.e. put on hold) the use of HES containing solutions
in routine clinical practice as a precautionary measure. Use in clinical trials
where patient selection is tightly controlled is still allowed. Of note, in
this clinical study, the HES containing solution is strictly used in the
allowed indication.
Study objective
To investigate non-inferiority regarding the safety of a 6% HES solution
(Volulyte 6%) versus an electrolyte solution (Ionolyte) in patients undergoing
elective abdominal surgery.
Study design
Prospective, randomized, controlled, double-blind, parallel-group,
multi-centric, multinational study
Intervention
Method of Administration:
The administration of the IPs is performed intravenously.
Dosage:
Dosing of IPs is individualized to the patient*s volume needs and guided by a
volume algorithm based on either mean arterial pressure or dynamic circulatory
parameters. The daily dose should not exceed 30 ml/kg. If patients are still
hypotensive during administration of IP, they may also receive vasoactive/
inotropic drugs, if regarded necessary due to the patients* clinical condition.
HES preparations for volume replacement may rarely cause allergic
(anaphylactic/anaphylactoid) reactions of varying degrees of severity.
In order to detect the occurrence of an allergic reaction as early as possible,
the first 10-20 ml of the solution should be infused slowly and
the patient should be under careful observation especially at the beginning of
the infusion. In case of an allergic reaction, the infusion
must be stopped immediately and appropriate treatment given.
If concomitant blood products are necessary, these should only be given
according to the most current version of the ESA guideline on the management of
severe perioperative bleeding.
Treatment Duration:
Patients will be treated for a maximum of 24 hours or until the maximum dose of
30 ml/kg body weight/day is reached, whatever occurs first.
If the patient is haemodynamically not yet stabilized after the maximum allowed
daily IP dosage of 30 ml/kg had been administered or 24 hours after IP
treatment start (whatever occurs first) only crystalloid solutions, or albumin
are to be administered. The choice of the solution is at the discretion of the
treating physician.
Study burden and risks
If the patient receives the investigational test product Volulyte 6 %, he/she
might possibly require a lower amount of plasma volume substitute to compensate
blood loss during surgery and to stabilise the circulatory system. This might
influence and reduce the occurrence of post-operative complications.
If the patient receives the investigational reference product Ionolyte,
participation in this clinical trial is not expected to affect the outcome of
the medical treatment.
All together, the participation in the clinical study will involve more
intensive, study-related monitoring and a considerable increase in
documentation. This may, taken by itself, result in an immediate benefit during
treatment.
The study itself poses no additional risks to the patient. The suspension of
clinical routine use does not apply to the use of Volulyte 6% in this clinical
trial, where patient selection is tightly controlled and used in the approved
indication. Participation in this clinical study will not impact the risks
associated with surgery.
As in the case of all infusions and blood collection procedures, damage to the
blood vessels and/or nerves, bruising, skin reactions and discomfort may occur
at the injection site.
Other risks are side effects of the plasma volume substitute that the patient
will receive during surgery.
All IPs have marketing authorizations in most European countries as well as in
various countries worldwide. For the investigational test product HES, a second
urgent union procedure under Article 107i of Directive 2001/83/EC
(EMEA/H/A-107i/1457) had started end of 2017 resulting in the recommendation
for a suspension (i. e. recommendation to put the market authorization *on
hold*, i. e. not revoked) of the market authorization of HES product in the EU.
The recommendation to suspend the market authorization is based on the
off-label use in certain patient populations (for example critically ill or
severe sepsis/ septic shock patients). This, however, does not affect the use
of HES in the present clinical trial in abdominal surgery patients, where
patient selection is not only tightly controlled but also is in line with the
registered SmPCs, the annex IV (*Conditions to the Marketing Authorisations
Holders*) of the *Recommendation of the Pharmacovigilance Risk Assessment
Committee pursuant to Article 107i of Directive 2001/83/EC*, and the
*Scientific Advice (EMA/CHMP/SAWP/544745/2014)*.
Furthermore, many of the proposed measures and parameters (laboratory,
clinical) are performed/obtained routinely and thus, do not represent major
additional burden to the patient.
In conclusion, the risk due to methods and measurements in the present study is
considered to be low and a balanced risk-benefit is assessed.
Battelsesteenweg 455D /
Mechelen 2800
BE
Battelsesteenweg 455D /
Mechelen 2800
BE
Listed location countries
Age
Inclusion criteria
* Male or female adult patients > 40 and * 85 years of age* Women of
childbearing potential must test negative on standard pregnancy test (urine or
serum)* Patients undergoing elective abdominal surgery with an expected blood
loss of * 500 ml* ASA Physical Status II-III* Signed written informed consent
form
Exclusion criteria
* Hypersensitivity to the active substances or to any of the other excipients
of the investigational
* medicinal products* Body weight * 140 kg* Sepsis* Burns* Renal impairment
(AKIN stage * 1 or chronic) or acute and/or chronic renal replacement therapy*
Intracranial or cerebral haemorrhage* Critically ill patients (typically
admitted to the intensive care unit)* Hyperhydration* Pulmonary oedema*
Dehydration* Hyperkalaemia* Severe hypernatraemia* Severe hyperchloraemia*
Severely impaired hepatic function* Congestive heart failure* Severe
coagulopathy* Organ transplant patients* Metabolic alkalosis* Simultaneous
participation in another interventional trial (drugs or medical device)
cacy of HES-containing solutions with re
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002162-30-NL |
| ClinicalTrials.gov | NCT03278548 |
| CCMO | NL59900.056.16 |