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).
Drug: ISIS 721744
1.2 mL of ISIS 721744 subcutaneous once after randomization
Drug: Normal Saline
1.2 mL subcutaneous
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
Hospital Naval Marcílio Dias
Rio De Janeiro, Brazil
BP-A Beneficiência Portuguesa de São Paulo
São Paulo, Brazil
Hospital São Paulo - UNIFESP
São Paulo, Brazil