Up to 1/3 of all patients infected with COVID-19 can develop complications that require hospitalization. Severe pneumonia associated with acute respiratory distress syndrome (ARDS) is the most threatening and feared complication of COVID-19 infection, with mortality rates close to 50% in some groups.

Autopsies between these severe cases reveal severe capillary involvement, with signs of intense inflammatory changes, microvascular thrombosis, endothelial injury and abnormal tissue repair. The available evidence suggests that abnormal activation or imbalance in the counter-regulation of the kallikrein-kinin system may play a central role in a positive feedback cycle, leading to consequent diffuse microangiopathy. Blockade of the kallikrein-kinin system can therefore prevent deterioration of lung function by reducing inflammation, edema and microthrombosis.

The objective of this phase IIb study is to assess the preliminary effects on the oxygenation parameters of an antisense oligonucleotide that inhibits pre-kallikrein synthesis in patients with moderate to severe COVID-19.

The objective of this phase IIb study is to assess the preliminary effects on the oxygenation parameters of an antisense oligonucleotide that inhibits pre-kallikrein synthesis in patients with moderate to severe COVID-19.

This is a blind randomized pilot clinical study which aims to include 110 patients (55 per arm).

Inclusion Criteria:

1. Patients with COVID-19 who need supplemental oxygen
2. Women must not be pregnant or breastfeeding, and must be surgically sterile or in the postmenopausal stage (without risk of becoming pregnant).
3. Men must be surgically sterile or abstinent or, if they are having sex with risk of pregnancy, the subject must use an effective method of contraception from the moment they sign the informed consent form until at least 24 weeks after the dose of the study drug (ISIS 721744 or placebo).

Exclusion Criteria:

1. Patients on invasive mechanical ventilation or who may need mechanical ventilation for the next 24 hours. The use of non-invasive ventilation and/or a high-flow nasal catheter is permitted.
2. Patients with > 10 days since symptom onset or more than 48h of oxygen use
3. Pregnancy, breast-feeding or risk of becoming pregnant
4. Hemodynamically unstable (use of vasoconstrictors, such as norepinephrine, at any dose)
5. Previous diagnosis of heart failure at functional class III or IV
6. Previous uncontrolled hypertension (more than 3 drug classes use at home)
7. Severe lung disease (use of home oxygen)
8. Age < 18 and > 80 years
9. Physician and family not committed to full life support and/or with severe existing illness with a life expectancy of less than 12 months
10. Refusal to accept informed consent and/or unwillingness to comply with all requirements of the study procedure and security monitoring

Data will be available under reasonable request after approval by the steering committee.

Protocol will be available in December, together with analysis plan

Protocol and analysis plan will be uploaded to Clinicaltrials.gov

The placebo used in the present study will consist of 0.9% NaCl Solution, which has the same physical characteristics as the ISIS 721744 drug. The placebo solution will be prepared by the nurse or pharmacist of the research team at the time of application. The nurse will be trained on the procedures for adequate blinding of the intervention. The pharmacist at the site level will not be blind, but the rest of the ream (nurse, physicians, patients, etc) will be blinded.