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Completed

NCT Number: NCT04549922

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

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.

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Key information

Conditions

Covid19 COVID-19 Coronaviridae Infections Coronavirus Infections Infections Lung Diseases Nidovirales Infections Pneumonia Pneumonia, Viral RNA Virus Infections Respiratory Tract Diseases Respiratory Tract Infections Virus Diseases

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Hospital Naval Marcílio Dias, Rio de Janeiro, Brazil

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About this study

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).

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

ISIS 721744

Drug

1.2 mL of ISIS 721744 subcutaneous once after randomization

normal saline

Drug

1.2 mL subcutaneous

Primary outcomes

  1. 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 outcomes

  1. 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.

  2. Need for mechanical ventilation

    Time frame: 30 days (or until hospital discharge)

    Intubation and initiation of mechanical ventilation for any given reason

  3. Duration of mechanical ventilation

    Time frame: 30 days (or until hospital discharge)

    Number of days the patient remains in mechanical ventilation

Other outcomes

  1. Oxygenation index

    Time frame: 14 days

    Daily oxygenation levels assessed using the ROX index [(Oxygen Saturation/Inspired Fraction)/Respiratory Rate] from randomization to discharge or day 14, whichever comes first.

  2. C-reactive protein levels during first 15 days after randomization

    Time frame: 15 days

    C-reactive protein levels over time up to 15 days or hospital discharge.

  3. Lymphocyte/neutrophil ratio during first 15 days after randomization

    Time frame: 15 days

    Lymphocyte/neutrophil ratio over time up to 15 or until discharge discharge day.

  4. D-dimer serum level during first 15 days after randomization

    Time frame: 15 days

    D-dimer serum levels over time or until hospital discharge.

  5. Fibrinogen serum levels during first 15 days after randomization

    Time frame: 15 days

    Fibrinogen serum levels over time up to 15 days or until hospital discharge

  6. Prothrombin Time levels during first 15 days after randomization

    Time frame: 15 days

    Prothrombin Time over time up to 15 days or until hospital discharge.

  7. Activated Partial Thromboplastin Time during first 15 days after randomization

    Time frame: 15 days

    Activated Partial Thromboplastin Time over time up to 15 days or until hospital discharge.

  8. Mortality

    Time frame: 1 year after randomization

    One-year all cause mortality

  9. Euroquol questionnaire for quality of life with 5 dimensions (EQ-5D)

    Time frame: 1 year after randomization

    Quality of Life measured by EQ-5D from 11111-33333, lower values being better

Sponsors and collaborators

Lead sponsor

Hospital do Coracao

Other

Collaborators

  • Hospital Moinhos de Vento
  • Ionis Pharmaceuticals, Inc.

Registry information

Official study title

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

Acronym: ASKCOV

Important dates

Study start
2020
Primary completion
2020
Study completion
2021
First posted
Sep 16, 2020
Registry last updated
Sep 22, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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