Study on Safety and Efficacy of Two Doses of PRS CK STORM in the Modulation of the Cytokine Storm in Patients With Acute Respiratory Infection Caused by SARS-Cov-2, Influenza A, Influenza B and Respiratory Syncytial Virus (RSV)

Double-blind, Randomized, Placebo-controlled, Pilot Clinical Trial to Evaluate the Safety, Tolerability and Efficacy of Two Doses of a Conditioned Medium From a Co-culture of M2-macrophages and Fat-derived Mesenchymal Cells (PRS CK STORM) in the Modulation of the Cytokine Storm in Patients With Acute Respiratory Infection Caused by SARS-Cov-2, Influenza A, Influenza B and Respiratory Syncytial Virus (RSV)

The purpose of this clinical trial is to evaluate the safety, tolerability and efficacy of two doses (dose A and dose B) of Standardized Conditioned Medium Obtained by Coculture of M2-macrophages and fat-derived Mesenchymal Stromal Cells (PRS CK STORM) in the modulation of the cytokine storm in participants with acute respiratory infection caused by SARS-Cov-2, influenza A, influenza B and respiratory syncytial virus (RSV) in need for oxygen therapy.

The main questions it aims to answer are:

• Are both doses of PRS CK STORM (dose A and dose B) safe as an intravenous drug to modulate inflammatory processes, such as the cytokine storm in participants with SIRS caused by SARS-Cov-2, influenza A, influenza B and RSV?
• Are both doses of PRS CK STORM (dose A and dose B) effective as an intravenous drug to modulate SIRS-associated cytokine storm caused by SARS-Cov-2, influenza A, influenza B and RSV compared to the control group?
• What are the anti-inflammatory and pro-inflammatory cytokine profiles after treatment with two different doses of PRS CK STORM in participants with SIRS caused by SARS-Cov-2, influenza A, influenza B and RSV?

Researchers will compare both doses of PRS CK STORM with the control group to test whether the anti-inflammatory action of PRS CK STORM is safe and effective in modulating the cytokine storm for the treatment of SIRS caused by SARS-Cov-2, influenza A, influenza B and RSV. In addition, the anti-inflammatory and pro-inflammatory cytokine profiles after treatment PRS CK STORM compared to placebo group in these participants will be also studied.

This is a double-blind, randomized, phase I/II pilot clinical trial of two doses of PRS CK STORM in adult participants with SIRS caused by SARS-Cov-2, influenza A, influenza B and RSV All participants will receive the standard of care for SIRS, according to its viral origin:

• Clinical management of COVID-19: hospital care (Centro de Coordinación de Alertas y Emergencias Sanitarias, 2020).
• Clinical practice guidelines for influenza (WHO, 2024). Participants who meet the eligibility criteria will be randomized in blocks to reach the 2:2:1 ratio (dose A: dose B: placebo).

This study consists of two parts:

Part 1: Doses A and B of PRS CK STORM will be evaluated in 2 groups of 4 participants (3:1; PRS CK STORM: placebo). It starts with a first sentinel group of 4 participants who will be assigned to placebo or study drug dose A. First, only 2 participants will randomly be assigned to receive the active treatment of dose A or placebo for 5 consecutive days. These 2 first participants will be followed up to 48h after the last drug administration (short-term safety follow-up period) when a safety assessment will be completed before treating the other 2 participants in this group.

If the study drug is considered safe during the short-term safety assessment planned 48h after the last drug administration, then 2 additional participants will be treated with dose A for 5 consecutive days to complete the first sentinel group of 4 participants. These 2 participants will be followed up to 48h after the last study drug administration before moving to dose B.

After the assessment of data collected follow-up for this first group, a second small sentinel group of other 4 participants will be treated with a higher dosage (dose B) following the same process, as long as dose A has been considered safe. First, only 2 participants will randomly receive the active treatment of dose B or placebo for 5 consecutive days and then these 2 first participants will be followed up to 48h after the last drug administration when a safety assessment will be completed before treating the other 2 participants in this group.

If the study drug is considered safe during the safety assessment planned 48h after last drug administration, then two additional participants will be treated with dose B for 5 consecutive days to complete the sentinel second group of 4 participants evaluating dose B. These 2 participants will be also followed up to 48h after the last study drug administration when a safety assessment will be completed before treating the other 2 participants in this group.

All these 8 participants included in Part 1 will continue in a long-term safety follow-up period until 1 year post treatment.

Part 2: 42 additional participants will be treated for 5 consecutive days. These 42 participants will be randomized to three treatment arms: 17 in the active arm with dose A, 17 participants in the active arm with dose B and 8 participants in the placebo arm. All participants in Part 2 will be followed up to 48h after the last study drug (short-term safety follow-up period). Once all participants treated in Part 2 finished the short-term safety follow-up period (48h after last study drug administration), all data will be verified and statistically analyzed in an interim analysis. All participants will be followed up to 1 year post treatment (long-term safety follow-up period). Therefore, considering the participants enrolled in Part 1 and Part 2 the total number of participants for safety, tolerability and efficacy analysis will be 50 assigned to three different arms (total randomization ratio 2:2:1), 20 participants will be assigned to dose A, 20 participants will be assigned to dose B and 10 participants will be assigned to placebo.

To sum up, considering the participants enrolled in Part 1 and Part 2 the total number of participants for safety, tolerability and efficacy analysis will be 50 assigned to three different arms (total randomization ratio 2:2:1), 20 participants will be assigned to dose A of PRS CK STORM, 20 participants will be assigned to dose B of PRS CK STORM and 10 participants will be assigned to placebo.

The estimated duration of the study for individual participants will be 12 months (screening: 3 days, treatment period: 5 days, short-term safety follow-up period: 2 days after the last drug intake and long-term safety follow-up period: up to 48 weeks from randomization).

It is hypothesized that both doses of PRS CK STORM for intravenous administration are safe, well tolerated and clinically beneficial versus placebo for participants with SIRS-associated cytokine storm.

Inclusion Criteria:

1. Signed informed consent by the participant or legal representative prior to the initiation of any study-specific procedure.

2. Males and females aged ≥ 18 years old at the time of the consent.

3. Confirmed diagnosis of SARS-CoV-2, influenza virus A, influenza virus B or RSV pneumonia by positive RT-PCR (results of a PCR prior to screening will be valid only if the PCR has been done for all 4 viruses and in 3 days prior to the screening visit). PCR will include the analysis of SARS-Cov-2, influenza A, influenza B and RSV.

4. Diagnosis of systemic inflammatory response syndrome (SIRS), defined by the satisfaction of any two of the criteria below:

   1. Body temperature over 38 ºC or under 36 ºC.
   2. Heart rate greater than 90 beats/minute.
   3. Respiratory rate higher than 20 breaths/min or PaCO2 lower than 32 mmHg.
   4. Leukocyte count higher than 12000/μL, lower than 4000/μL or over 10% immature forms or bands.

5. Need for oxygen therapy.

6. Female participants must be, either surgically sterilized or at least 1 year postmenopausal (confirmed by follicle-stimulating hormone [FSH] more than 20 international units [Ius] only for women under 54) or using adequate birth control (hormonal contraception, intrauterine contraceptive device, double barrier methods [condom with spermicide, diaphragm with spermicide, or condom and diaphragm]) or sexual abstinence for up to 90 days after the last treatment administration. Male participants must be willing to use barrier contraception (condom) for up to 90 days after the last treatment administration.

Exclusion Criteria:

1. Failure to perform screening or baseline examinations.

2. Body Mass Index (BMI) more than or equal to 35.

3. Irreversible critical condition, as assessed by the investigator.

4. Active autoimmune diseases or severe immunosuppression, unless stable and controlled for at least 3 months prior to the inclusion in the study.

5. Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations, may bias the clinical assessment, such as:

   1. Liver function test abnormalities or other signs of hepatic insufficiency not justified by a pulmonary acute inflammation process: Aspartate transaminase (AST), alanine transaminase (ALT) more than 3 per upper limit of the reference range, total bilirubin more than or equal to 2 mg/dL; except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome.
   2. Renal insufficiency (serum creatinine more than 2 mg/dL (more than 150 μmol/L) and creatinine clearance less than 30 (according to Cockcroft-Gault formula).
   3. Myocardial infarction, unstable angina, heart failure within 3 months before screening.
   4. Bradycardia (heartbeat less than 50/min).
   5. Atrioventricular block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcF interval (males more than 450 msec and females more than 470 msec using Fridericia's formula: QTc = QT/ RR^2 ).
   6. Uncontrolled diabetes mellitus (blood glucose level above 500 mg/dL) at the time of admission.
   7. Malignant tumors within the last 5 years, unless stable during that time. Skin malignancies (other than melanoma) and indolent prostate cancer are excluded from this criterion.
   8. Metastases.
   9. Human Immunodeficiency Virus (HIV), HBV [hepatitis B surface antigen (HBs Ag) positive (+), or detected sensitivity on the HBV deoxyribonucleic acid (DNA), polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody (HBc Ab) positive subjects] or HCV [HCV ribonucleic acid (RNA) detectable in any subject with positive anti-HCV antibody (HCV Ab)].

6. Inability to comply with the study and monitoring procedures.

7. Pregnant and breastfeeding females (pregnancy test positive).

8. Suspected or known active drug or alcohol abuse.

9. Enrollment in another investigational drug study within 1 month before the screening

10. Subject who has any condition, including any psychological or psychiatric condition, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data and renders the subject an unsuitable candidate for the study.