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

Overview

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.

Full Title of Study: “Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: February 2021

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 90 patients (45 per arm).

Interventions

  • Drug: ISIS 721744
    • 1.2 mL of ISIS 721744 subcutaneous once after randomization
  • Drug: Normal Saline
    • 1.2 mL subcutaneous

Arms, Groups and Cohorts

  • Placebo Comparator: Placebo
    • 1.2 mL Normal Saline, single dose subcutaneous, after randomization
  • Active Comparator: ISIS 721744
    • 1.2 mL ISIS 721744, single dose subcutaneous, after randomization

Clinical Trial Outcome Measures

Primary Measures

  • Days alive without respiratory support (any supplemental oxygen) after 15 days (DAFOR15)
    • Time Frame: 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 Measures

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

Participating in This Clinical Trial

Inclusion Criteria

1. Patients with COVID-19 who need supplemental oxygen of at least 2L/min (≥ 2L/min) through a nasal catheter (or equivalent) to obtain a peripheral oxygen saturation ≥ 95%

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 > 7 days since symptom onset

3. Pregnancy, breast-feeding or risk of becoming pregnant

4. Hemodynamically unstable (use of vasoconstrictors, such as norepinephrine, above 0.1 mcg/kg/min)

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Hospital do Coracao
  • Collaborator
    • Ionis Pharmaceuticals, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Fernando G Zampieri, MD, Principal Investigator, Research Coordinator
    • Alexandre B Cavalcanti, Study Chair, Institute Director
  • Overall Contact(s)
    • Fernando G Zampieri, MD, +551130656611, fzampieri@hcor.com.br

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