Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19

Study Overview
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Brief Summary
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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
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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).

Official Title
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Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial

Conditions
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Covid19

Intervention / Treatment
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* Drug: ISIS 721744
* Drug: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with COVID-19 who need supplemental oxygen Women must not be pregnant or breastfeeding, and must be surgically sterile or in the postmenopausal stage (without risk of becoming pregnant). 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: 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. Patients with > 10 days since symptom onset or more than 48h of oxygen use Pregnancy, breast-feeding or risk of becoming pregnant Hemodynamically unstable (use of vasoconstrictors, such as norepinephrine, at any dose) Previous diagnosis of heart failure at functional class III or IV Previous uncontrolled hypertension (more than 3 drug classes use at home) Severe lung disease (use of home oxygen) Age < 18 and > 80 years Physician and family not committed to full life support and/or with severe existing illness with a life expectancy of less than 12 months Refusal to accept informed consent and/or unwillingness to comply with all requirements of the study procedure and security monitoring

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>1.2 mL Normal Saline, single dose subcutaneous, after randomization | Drug: Normal Saline<br>* 1.2 mL subcutaneous<br>|
| Active Comparator: ISIS 721744<br>1.2 mL ISIS 721744, single dose subcutaneous, after randomization | Drug: ISIS 721744<br>* 1.2 mL of ISIS 721744 subcutaneous once after randomization<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days alive without respiratory support (any supplemental oxygen) after 15 days (DAFOR15) | Number of days the patient is alive and not receiving any supplementary respiratory support (oxygen, non-invasive ventilation, high flow nasal catheter or mechanical ventilation) during 15 days | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SOFA - Sequential Organ Failure Assessment Score up to 15 days after randomization | Sequential Organic Failure Assessment [SOFA]. This will be a primary secondary outcome. Analysis will check for trends in SOFA up to 15 days in a single model. | 15 days | 
| Need for mechanical ventilation | Intubation and initiation of mechanical ventilation for any given reason | 30 days (or until hospital discharge) | 
| Duration of mechanical ventilation | Number of days the patient remains in mechanical ventilation | 30 days (or until hospital discharge) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antisense, kallikrein-kinin