Clinical trial NCT04549922: Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19
Official title: Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Covid19
Keywords: antisense
kallikrein-kinin
Lead sponsor: Hospital do Coracao
Sponsor class: OTHER
Collaborators: name: Ionis Pharmaceuticals, Inc.
name: Hospital Moinhos de Vento
First posted: 2020-09-16
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Days alive without respiratory support (any supplemental oxygen) after 15 days (DAFOR15)
timeFrame: 15 days
Secondary outcomes:
measure: SOFA - Sequential Organ Failure Assessment Score up to 15 days after randomization
timeFrame: 15 days
measure: Need for mechanical ventilation
timeFrame: 30 days (or until hospital discharge)
measure: Duration of mechanical ventilation
timeFrame: 30 days (or until hospital discharge)
Other outcomes:
measure: Oxygenation index
timeFrame: 14 days
measure: C-reactive protein levels during first 15 days after randomization
timeFrame: 15 days
measure: Lymphocyte/neutrophil ratio during first 15 days after randomization
timeFrame: 15 days
measure: D-dimer serum level during first 15 days after randomization
timeFrame: 15 days
measure: Fibrinogen serum levels during first 15 days after randomization
timeFrame: 15 days
measure: Prothrombin Time levels during first 15 days after randomization
timeFrame: 15 days
measure: Activated Partial Thromboplastin Time during first 15 days after randomization
timeFrame: 15 days
measure: Mortality
timeFrame: 1 year after randomization
measure: Euroquol questionnaire for quality of life with 5 dimensions (EQ-5D)
timeFrame: 1 year after randomization
Locations:
city: Rio De Janeiro
country: Brazil
facility: Hospital Naval Marcílio Dias
city: São Paulo
country: Brazil
facility: BP-A Beneficiência Portuguesa de São Paulo
city: São Paulo
country: Brazil
facility: Hospital São Paulo - UNIFESP
Study officials:
affiliation: Research Coordinator
name: Fernando G Zampieri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute Director
name: Alexandre B Cavalcanti
role: STUDY_CHAIR
References: