Safety and Preliminary Clinical Activity of Itolizumab in ARDS

A Phase 1 Study to Evaluate the Safety, Tolerability and Preliminary Clinical Activity of Itolizumab in Subjects With Acute Respiratory Distress Syndrome Caused by Infectious Pneumonia

To evaluate the safety, tolerability, PK, PD, and clinical activity of Itolizumab in subjects with acute respiratory distress syndrome (ARDS) caused by Infectious Pneumonia.

The study will enroll approximately 38 subjects in two parts:

Part 1 is an open label 3+3 single dose escalation phase. 9-24 patients with ARDS caused by infectious pneumonia across 3 dose cohorts.

Part 2 is a randomized phase and will enroll approximately 14 additional participants, randomized in a 1:1 ratio to one of the 2 doses based on efficacy data obtained from Part 1.

All participants in this study will receive Itolizumab intravenously for once, investigator discretion to continue with the same dose every 3 days up to 7 days.

Inclusion Criteria:

1. Male or female subject aged 18-75 years old (inclusive)
2. Clinical diagnosis with infectious pneumonia as determined by the investigator
3. Subject who havd received anti-infective treatment according to clinical practice.
4. Diagnosis with ARDS according to the following criteria: (i) Bilateral opacities-not fully explained by effusions, lobar/lung collapse, or nodules; (ii) respiratory failure not fully explained by cardiac failure or fluid overload; (iii) Oxygenation (PaO2/FiO2) ≤300.
5. ARDS diagnosed within 48 hours before administration, and fullfil the criteria of ARDS before administration
6. Fullfill at least 2 of the following 4 criteria: ① elevated hs-CRP (>6 ULN); ② elevated IL-6 (>3 ULN); ③ high serum ferritin (>500µg/L at any one time or more than 2-fold increase within 48 hours of onset); ④ high D-dimer (>3 ULN).
7. Negative result of serum HCG within 72 hours before enrollment for female with potential fertility
8. Participant or his/her legal representive (when the participant is not capable of giving consent) is able to understand and comply with the planned procedure as required by the protocol, and sign a written informed consent form (ICF)

Exclusion Criteria:

1. ARDS caused by non-infectious pneumonia (e.g., burns, drowning, poisoning, etc.)

2. Subject who has cardiogenic pulmonary edema, and it is the main cause of respiratory failure

3. Subject who is at high risk of death within 24 hours regardless of the treatment measures given as determined by the investigator

4. Subject who is receiving extracorporeal membrane pulmonary oxygenation (ECMO) therapy at the time of screening.

5. Subject who had received mechanical ventilation for more than 72 hours prior to administration.

6. Subject with active tumors (other than carcinoma in situ or basal cell carcinoma) that requiring treatment.

7. Any of the following chronic organ damage or immunosuppression:

   1. Cardiac: cardiac arrest within 7 days prior to screening; New York Heart Association cardiac function class IV at screening;
   2. Pulmonary: oxygen therapy or ventilator-dependent therapy for more than 1 month cumulatively within 6 months prior to screening; pulmonary embolism within 4 weeks prior to screening; pulmonary hypertension, end-stage lung disease, or interstitial lung disease requiring glucocorticoid therapy at screening;
   3. Renal: serum creatinine > 1.5 ULN or creatinine clearance < 30 mL/min at screening (Cockcroft-Gault formula, see study protocol annex 5 for details) or on long-term dialysis treatment;
   4. Liver: liver function classification of Child-Pugh grade C at screening;
   5. Immunosuppression status: with lymphoma, leukemia or acquired immunodeficiency; having received antitumor chemotherapy in the last 3 months, or being treated with immunosuppression for organ transplantation or immune disorders; having had allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation.

8. Subject who had vaccination within 28 days prior to administration, or plan to get the vaccine during the study period

9. Any of the following abnormalities at screening

   1. Hepatitis B-related tests: ① positive for hepatitis B surface antigen (HBsAg); ② positive for hepatitis B core antibody (HBcAb); ③ positive for hepatitis B surface antibody (HBsAb) and no history of hepatitis B vaccination; ④ positive for hepatitis B e antigen or hepatitis B e antibody;
   2. Positive hepatitis C virus antibody (HCV-Ab);
   3. Positive acquired immunodeficiency syndrome antibody (HIV-Ab).

10. Subject who has a medical history of tuberculosis or those who deny a history of tuberculosis but has a positive gamma-interferon release test at screening.

11. Absolute lymphocyte count < 0.2×109/L at screening

12. Suspected allergic to the investigational drug or any of its excipients

13. Currently pregnant, breastfeeding,or planning to become pregnant or not using reliable method to avoid pregnancy during study and within 3 months after the last study treatment

14. Subject who had participated in other clinical studies (other than those not receiving interventions, such as observational study or questionnaires survey) within 3 months prior to screening, or who are participating in other experimental treatments.

15. As determined by the investigator, any medical, psychiatric, or other condition or circumstance that is likely to negatively affect the reliability of the study data.