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

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Normal Saline; Drug: ISIS 721744

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 Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio De Janeiro, Brazil
    • Hospital Naval Marcílio Dias
  • São Paulo, Brazil
    • Hospital São Paulo - UNIFESP
  • São Paulo, Brazil
    • BP-A Beneficiência Portuguesa de São Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 1.2 mL Normal Saline, single dose subcutaneous, after randomization	Drug: Normal Saline; 1.2 mL subcutaneous
Active Comparator: ISIS 721744; 1.2 mL ISIS 721744, single dose subcutaneous, after randomization	Drug: ISIS 721744; 1.2 mL of ISIS 721744 subcutaneous once after randomization

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygenation index	Daily oxygenation levels assessed using the ROX index [(Oxygen Saturation/Inspired Fraction)/Respiratory Rate] from randomization to discharge or day 14, whichever comes first.	14 days
C-reactive protein levels during first 15 days after randomization	C-reactive protein levels over time up to 15 days or hospital discharge.	15 days
Lymphocyte/neutrophil ratio during first 15 days after randomization	Lymphocyte/neutrophil ratio over time up to 15 or until discharge discharge day.	15 days
D-dimer serum level during first 15 days after randomization	D-dimer serum levels over time or until hospital discharge.	15 days
Fibrinogen serum levels during first 15 days after randomization	Fibrinogen serum levels over time up to 15 days or until hospital discharge	15 days
Prothrombin Time levels during first 15 days after randomization	Prothrombin Time over time up to 15 days or until hospital discharge.	15 days
Activated Partial Thromboplastin Time during first 15 days after randomization	Activated Partial Thromboplastin Time over time up to 15 days or until hospital discharge.	15 days
Mortality	One-year all cause mortality	1 year after randomization
Euroquol questionnaire for quality of life with 5 dimensions (EQ-5D)	Quality of Life measured by EQ-5D from 11111-33333, lower values being better	1 year after randomization

Collaborators and Investigators

• Sponsor: Hospital do Coracao
• Collaborators: Ionis Pharmaceuticals, Inc.; Hospital Moinhos de Vento
• Investigators: Principal Investigator: Fernando G Zampieri, MD, Research coordinator; Study Chair: Alexandre B Cavalcanti, institute director

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2020
• Primary Completion (Actual): December 9, 2020
• Study Completion (Actual): December 9, 2021

Study Registration Dates

• First Submitted: September 9, 2020
• First Submitted That Met QC Criteria: September 11, 2020
• First Posted (Actual): September 16, 2020

Study Record Updates

• Last Update Posted (Actual): September 22, 2022
• Last Update Submitted That Met QC Criteria: September 21, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: antisense; kallikrein-kinin
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: ASKCOV_Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data will be available under reasonable request after approval by the steering committee.
• IPD Sharing Time Frame: Protocol will be available in December, together with analysis plan
• IPD Sharing Access Criteria: Protocol and analysis plan will be uploaded to Clinicaltrials.gov
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No