This is a randomized, double-blind, placebo-controlled dose-selection study in which two doses of nangibotide are tested versus placebo.

All patients with a diagnosis of septic shock will be considered for study participation. All potential study patients will receive standard of care for the treatment of septic shock.

After screening for eligibility, patients meeting all inclusion and no exclusion criterion will be randomized. Patients will be randomized to one of three treatment arms.

Treatment with study drug must be initiated as early as possible, but no later than 24 hours after the onset of septic shock, defined by the start of vasopressor therapy.

Patients will be treated for at least 3 days with study drug. After the first 3 days of treatment, patients still requiring vasopressor will be treated until 24 hours after vasopressor withdrawal with a maximum treatment duration of 5 days.

Patients will be assessed at the End of Study (EoS) visit at day 28. After the last patient's day 28 visit, the study will be analyzed. Additional follow up (FU) visits will be conducted after 90 days, 6 and 12 months.

The objective of the study ist to compare the safety, tolerability and efficacy of two doses of nangibotide versus placebo, when given in addition to standard of care.

Inclusion Criteria:

1. Provide written informed consent
2. Age 18 to 85 years (inclusive)
3. Documented or suspected infection: lung, abdominal or urinary tract infection (UTI) in the elderly (≥65 years)
4. Organ dysfunction defined as acute change in total SOFA score ≥ 2 points
5. Refractory hypotension requiring vasopressors to maintain MAP ≥65mm Hg despite adequate volume resuscitation
6. Hyperlactatemia (blood lactate >2 mmol/L or 18 mg/dL).

Exclusion Criteria:

1. Previous episode of septic shock requiring vasopressor administration within current hospital stay
2. Underlying concurrent immunodepression with anti-CD52 alemtuzumab (Campath) or glucocorticoids >75 mg prednisone daily or equivalent for more than 7 days
3. Immunosuppressive therapy related to recent (<6 months) transplantation
4. Cancer chemotherapy (<3 months) implying an immunodepression
5. Known HIV infection with low CD4 cell count (<200) for at least 6 months
6. Known pregnancy (positive urine or serum pregnancy test)
7. Shock of any other cause, e.g. hypotension related to gastrointestinal bleeding
8. Ongoing documented or suspected endocarditis, history of prosthetic heart valves
9. Prolonged QT syndrome
10. End-stage neurological disease
11. End-stage cirrhosis (Child Pugh Class C)
12. Acute Physiology and Chronic Health Evaluation (APACHE II) score <15 or ≥ 34
13. Home oxygen therapy on a regular basis for > 6 h/day
14. Recent cardiopulmonary resuscitation (CPR) (within current hospital stay)
15. Body mass index (BMI) ≥ 40 kg/m2or weight ≥ 130 kg
16. Moribund patients
17. Decision to limit full care taken before obtaining informed consent
18. Participation in another interventional study in the 3 months prior to randomization