VOLU-011-C P4

Fresenius Kabi Deutschland GmbH

Else-Kroener-Str. 1, Bad Homburg, Germany, 61352

Division Medical & Clinical Affairs Generics & Standard Solutions, Volume Therapy, Fresenius Kabi Deutschland GmbH, scientific-contact@fresenius-kabi.com

Division Medical & Clinical Affairs Generics & Standard Solutions, Volume Therapy, Fresenius Kabi Deutschland GmbH, scientific-contact@fresenius-kabi.com

No

No

No

Final

19 Aug 2014

Yes

13 Sep 2013

Yes

13 Sep 2013

Yes

This explorative pilot trial compared 2 burn fluid resuscitation regimes (supplementation with 6% hydroxyethyl starch (HES) 130/0.4 in a balanced isotonic electrolyte solution, Volulyte 6%, versus supplementation with human serum albumin (HSA) 50g/L on outcome with particular regard to fluid balance at 24 hours after burn injury (primary variable).

Written Informed Consent/Assent was received from all patients/relatives/ independent physicians prior to enrolment into the trial, as dictated by the Declaration of Helsinki. In the setting of major burns, a positive vote was required (in accordance with the local ethical guidelines) to permit enrolment of unconscious patients in an emergency situation, where assent was sought from the legal representative prior to enrolment. Surviving patients were informed of the trial as soon as possible after enrolment. A legal representative could be a personal or a nominated legal representative. A personal legal representative could be a relative (next-of-kin) or friend who gave assent representing the patient’s presumed will. A nominated legal representative could be a doctor responsible for patient’s treatment or nominated by the healthcare provider. Both could not be connected with the trial. The investigator was responsible for giving each patient/legal representative full and adequate verbal and written information about the objectives and procedures of the trial and the potential benefits, discomforts, and risks involved prior to inclusion in the trial. An independent data monitoring committee (IDMC) with a purpose of a data safety monitoring board (DSMB) was implemented in this phase IV trial to ensure that there would be no unavoidable risk for harm for patients in any of the 2 treatment groups. As part of the trial, 2 physicians (both anaesthesiologists) with relevant training reviewed the data from the trial on a routine basis for safety assessments. The DSMB was restricted to individuals free of significant conflicts of interest. The DSMB met a total of 3 times during the conduct of the trial. At the final meeting the DSMB concluded that there were no safety concerns.

02 Dec 2012

No

Yes

United Kingdom: 9

9

9

0

0

0

0

0

0

9

0

0

Overall Trial (overall period)

Randomised - controlled

Yes

Volulyte 6% Solution for Infusion

6% hydroxyethyl starch 130/0.4 in an isotonic electrolyte solution

Solution for infusion

Intravenous use

Randomisation was within 8 hours after burn injury. Within the first 24 hours after burn injury, both treatment arms received up to 2 mL/kg/% total body surface area (TBSA) Hartmann’s Lactated Ringer’s solution (LR) as per modified Parkland regime (including the initial treatment phase from rescue to arrival at the hospital). Patients in the Volulyte 6%-supplemented arm received 250 mL Volulyte 6% boluses (after randomisation) as required to achieve haemodynamic goals, in addition to Hartmann’s (LR) infusion, during the 0 to 24 hours after burn injury. The total volume of Volulyte 6% infusion was not to exceed 50 mL/kg/24 hours. For patients who failed to respond to the above and/or in whom the maximum daily dosage of Volulyte 6% had been reached but still more fluid was required, the investigator was recommended to proceed with Hartmann’s (LR) or give vasoactive drugs.

Albunorm 5%, 50 g/L, solution for infusion

human serum albumin 50 g/L

Solution for infusion

Intravenous use

Randomisation was within 8 hours after burn injury. Within the first 24 hours after burn injury, both treatment arms received up to 2 mL/kg/% total body surface area Hartmann’s (LR) as per modified Parkland regime (including the initial treatment phase from rescue to arrival at the hospital). Patients in the albumin-supplemented arm received 250 mL Hartmann’s (LR) boluses after randomisation as required to achieve haemodynamic goals, in addition to Hartmann’s (LR) infusion, during the 0 to 8 hours after burn injury. A patient was also allowed to receive 5% albumin boluses as rescue colloid at the investigator’s discretion. During the 8 to 24 hours after burn injury, 250 mL 5% albumin (HSA 50 g/L) boluses were administered as required to achieve haemodynamic goals in addition to Hartmann`s (LR) infusion. There was no daily dose limit. For patients who failed to respond to the pure crystalloid or crystalloid/albumin regime, the investigator was allowed to give vasoactive drugs.

Volulyte

Human Serum Albumin

mITT Population

The modified intent-to-treat population (mITT) consisted of all patients in the ITT population (patients who were randomised) for whom the primary variable (fluid balance at 24 hours after burn injury) was evaluable and that were analysed according to actual treatment. Following the database lock 2 violations regarding the treatment allocation were detected. One male patient was randomised to the HSA arm but treated with Volulyte while another male patient was randomised to the Volulyte arm but treated with HSA. Therefore, the total number of patients for analysis of ITT and mITT population was not affected.

Safety Population

The safety population consisted of all randomised patients who received at least 1 dose of randomised study medication.

Volulyte

Human Serum Albumin

mITT Population

The modified intent-to-treat population (mITT) consisted of all patients in the ITT population (patients who were randomised) for whom the primary variable (fluid balance at 24 hours after burn injury) was evaluable and that were analysed according to actual treatment. Following the database lock 2 violations regarding the treatment allocation were detected. One male patient was randomised to the HSA arm but treated with Volulyte while another male patient was randomised to the Volulyte arm but treated with HSA. Therefore, the total number of patients for analysis of ITT and mITT population was not affected.

Safety Population

The safety population consisted of all randomised patients who received at least 1 dose of randomised study medication.

The primary efficacy endpoint of this trial was the cumulative fluid balance (input-output) at 24 hours after burn injury.

Primary

24 Hours after Burn Injury

Mortality was continuously evaluated until day 28

Secondary

28 calendar days after burn injury

Mortality was continuously evaluated until day 90

Secondary

90 calendar days after burn injury

Adverse events were recorded throughout the trial at any time from admission to burns unit on T0 (≤ 8 hours after burn injury) until last subject last visit on T10 (day 90)

For this trial only treatment-emergent adverse events (TEAEs), i.e. adverse events (AEs) including serious AEs that began or worsened after the start of study medication, were reported and summarised in tables. Thus the number of serious and non-serious AEs below reflects the number of serious and non-serious TEAEs.

16.1

Volulyte

Human Serum Albumin

Safety Population