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

Phase 2

Completed

• Conditions: Covid19
• Interventions: Drug: Normal Saline; Drug: ISIS 721744

• Registration Number: NCT04549922
• Lead Sponsor: Hospital do Coracao

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).

Study Timeline

• Study First Submitted: 2020-09-09
• Study First Submitted QC: 2020-09-11
• Study First Posted: 2020-09-16
• Study Start: 2020-10-19
• Primary Completion: 2020-12-09
• Study Completion: 2021-12-09
• Status Verified: 2022-09
• Last Update Submitted: 2022-09-21
• Last Update Posted: 2022-09-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 111

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Normal Saline	1.2 mL Normal Saline, single dose subcutaneous, after randomization
ISIS 721744	ISIS 721744	1.2 mL ISIS 721744, single dose subcutaneous, after randomization

Primary Outcome Measures

Name	Time	Method
Days alive without respiratory support (any supplemental oxygen) after 15 days (DAFOR15)	15 days	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

Secondary Outcome Measures

Name	Time	Method
SOFA - Sequential Organ Failure Assessment Score up to 15 days after randomization	15 days	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.
Need for mechanical ventilation	30 days (or until hospital discharge)	Intubation and initiation of mechanical ventilation for any given reason
Duration of mechanical ventilation	30 days (or until hospital discharge)	Number of days the patient remains in mechanical ventilation

Trial Locations

Locations (3)

Hospital São Paulo - UNIFESP; 🇧🇷 São Paulo, Brazil

Hospital Naval Marcílio Dias; 🇧🇷 Rio De Janeiro, Brazil

BP-A Beneficiência Portuguesa de São Paulo; 🇧🇷 São Paulo, Brazil