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

NCT04549922 | Completed Phase 2 DMC

• 1 other identifier: ASKCOV_Trial
• Study Type: interventional
• Target: 111
• Locations: 1 country
• Sites: 3

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.

Conditions

Covid19

Keywords

antisense; kallikrein-kinin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• SOFA - Sequential Organ Failure Assessment Score up to 15 days after randomization

  15 days

• Need for mechanical ventilation

  30 days (or until hospital discharge)

• Duration of mechanical ventilation

  30 days (or until hospital discharge)

Other Outcomes (9)

• Oxygenation index

  14 days

• C-reactive protein levels during first 15 days after randomization

  15 days

• Lymphocyte/neutrophil ratio during first 15 days after randomization

  15 days

Study Arms (2)

Placebo

PLACEBO COMPARATOR

1.2 mL Normal Saline, single dose subcutaneous, after randomization

Drug: Normal Saline

ISIS 721744

ACTIVE COMPARATOR

1.2 mL ISIS 721744, single dose subcutaneous, after randomization

Drug: ISIS 721744

Interventions

ISIS 721744 DRUG

1.2 mL of ISIS 721744 subcutaneous once after randomization

ISIS 721744

Normal Saline DRUG

1.2 mL subcutaneous

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Hospital do Coracao: lead
• Ionis Pharmaceuticals, Inc.: collaborator
• Hospital Moinhos de Vento: collaborator

Study Sites (3)

Hospital Naval Marcílio Dias

Rio de Janeiro, Brazil

Location

BP-A Beneficiência Portuguesa de São Paulo

São Paulo, Brazil

Location

Hospital São Paulo - UNIFESP

São Paulo, Brazil

Location

Related Publications (1)

• Zampieri FG, Westphal GA, Santos MAD, Gomes SPC, Gomes JO, Negrelli KL, Santos RHN, Ishihara LM, Miranda TA, Laranjeira LN, Valeis N, Santucci EV, de Souza Dantas VC, Gebara O, Cohn DM, Buchele G, Janiszewski M, de Freitas FG, Dal-Pizzol F, de Matos Soeiro A, Berti IR, Germano A, Schettini DA, Rosa RG, Falavigna M, Veiga VC, Azevedo LCP, Damiani LP, Machado FR, Cavalcanti AB; BRICNet. Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial. J Crit Care. 2024 Dec;84:154892. doi: 10.1016/j.jcrc.2024.154892. Epub 2024 Aug 3.

  PMID: 39096659 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Saline Solution

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Fernando G Zampieri, MD

  Research Coordinator

  PRINCIPAL INVESTIGATOR

• Alexandre B Cavalcanti

  Institute Director

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The placebo used in the present study will consist of 0.9% NaCl Solution, which has the same physical characteristics as the ISIS 721744 drug. The placebo solution will be prepared by the nurse or pharmacist of the research team at the time of application. The nurse will be trained on the procedures for adequate blinding of the intervention. The pharmacist at the site level will not be blind, but the rest of the ream (nurse, physicians, patients, etc) will be blinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2020
• First Posted: September 16, 2020
• Study Start: October 19, 2020
• Primary Completion: December 9, 2020
• Study Completion: December 9, 2021
• Last Updated: September 22, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Protocol will be available in December, together with analysis plan
• Access Criteria: Protocol and analysis plan will be uploaded to Clinicaltrials.gov

Locations

BR (3)