ASSET - a Double-Blind, Randomized Placebo-Controlled Clinical Investigation With Alteco® LPS Adsorber

Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) - a Double-Blind, Randomized Placebo-Controlled Clinical Investigation With Alteco® LPS Adsorber

The primary objective of this clinical investigation is to investigate the feasibility and possible benefits of the Alteco® LPS Adsorber in treating patients with septic shock with presumed endotoxemia of abdominal or urogenital origin.

OVERALL CLINICAL INVESTIGATION DESIGN:

This is a multicentre, stratified, parallel, double-blinded, randomized, feasibility clinical investigation of the Alteco® LPS Adsorber.

Subjects will be enrolled in an adaptive fashion with up to two interim analyses, and the possibility of recruiting additional patients, in order to establish an indication of the feasibility of treating a target population of subjects with septic shock and endotoxemia.

Subjects will be stratified in accordance with the origin of their infection, i.e. abdominal or urogenital sepsis. Subjects in each stratum will receive either:

• LPS Adsorber group (i.e. investigational medical device [IMD] group): current best practice in combination with Alteco® LPS Adsorber treatment, OR
• Placebo device group (i.e. comparator group): current best practice in combination with placebo adsorber treatment.

Allocation to either treatment arm will be performed in a 1:1 ratio. Upon enrolment (i.e. pre-treatment phase), subjects admitted to the ICU with suspected endotoxemia will be screened for fulfilment of the "Illness Severity Criteria" confirming early stage severe sepsis.

Within six (6) hours of enrolment, subjects who also fulfil the "Treatment Criteria" confirming septic shock will be eligible for randomization.

Randomization to either of the treatment groups will be performed as close as possible to start of treatment with the Alteco® LPS Adsorber or placebo device.

Treatment with LPS Adsorber or placebo device must be initiated within six (6) hours (Day 1) following fulfilment of the "Treatment Criteria". A second device treatment will be performed 24 hours after the end of the first device treatment on Day 2, as long there is no evidence that treatment with the investigational device will not be beneficial or will indicate an unnecessary risk for subjects (for example, the subject is vasopressor support-free).

Initially: 20 abdominal sepsis subjects (Stratum A) and 12 urogenital sepsis subjects (Stratum B) Optional: additional 12 subjects (abdominal, urogenital or both) after interim analysis decision.

Inclusion Criteria:

Illness severity criteria: At enrolment subjects must meet inclusion criteria #1 through #3 listed below to be eligible to enter the clinical investigation:

1. Subjects must have suspected severe infection of abdominal or urogenital origin for which the subject is receiving intravenous antimicrobial therapy as the main reason for organ support

2. Subjects, males or females, must be 18 years or older.

3. Subjects or legally acceptable representatives, as appropriate, are willing and able to provide signed informed consent.

   Treatment criteria: Prior to randomization, subjects must meet all inclusion criteria (#4 through #7) listed below to be assigned to a treatment group:

4. Appropriate vascular access must have been obtained.

5. Subjects must have received ≥ 30 mL/kg of intravenous fluid within the six (6) hours prior to randomization.

6. Subjects must have plasma/serum lactate >2 mmol/L despite adequate resuscitation AND a continuous requirement for vasopressor support

7. Subjects must be able to initiate the clinical investigation intervention within 12 hours of fulfilment of the illness severity criteria.

Exclusion Criteria:

1. Subjects who meet any of the exclusion criteria listed below will NOT be permitted to enter the clinical investigation: Sepsis-induced organ dysfunction for longer than 12 hours prior to the time-point for achieving "Illness severity criteria fulfilled"

2. Vasopressor therapy (at any dose) for longer than 12 hours (not included the time spent in the operation theatre) prior to the start of treatment with the investigational device.

3. Pre-existing uncorrectable medical condition as:

   • Poorly controlled neoplasms or hematologic disease (i.e. indication of disseminated cancer outside the suspected primary tumour and hematologic disease not in remission,
   • End-stage cardiac disease,
   • Cardiac arrest requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole within the past 7 days
   • End-stage lung disease
   • End-stage liver disease
   • HIV/AIDS with known end-stage processes
   • Other uncorrectable medical condition(s) deemed by the Clinical Investigator to hinder the subject to adhere to the fulfilment of the activities described in the Clinical Investigation Plan.

4. Extreme illness, i.e. subjects is moribund and death is perceived to be imminent (within 24 hours).

5. Recent or current participation (≤ 30 days) in another interventional sepsis trial.

6. Recent or current treatment (≤ 30 days) with an adsorption product, including Alteco® LPS Adsorber.

7. Treatment with an investigational medicinal product for any indication within the last 30 days before enrolment in the clinical investigation.

8. Pregnancy.

9. Contraindications to the use heparin or protamine

10. Other abdominal inflammatory conditions

11. Perforation of hollow organ linked to trauma within 48 hours before enrolment in the clinical investigation.

12. Laparotomy reveals isolated gastric ulcer.

13. Subjects and/or their immediate family are directly affiliated to investigative site personnel in this clinical investigation. (Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted).