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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04549922
Recruitment Status : Recruiting
First Posted : September 16, 2020
Last Update Posted : October 27, 2020
Sponsor:
Collaborators:
Ionis Pharmaceuticals, Inc.
Hospital Moinhos de Vento
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Covid19 Drug: ISIS 721744 Drug: Normal Saline Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial
Estimated Study Start Date : October 21, 2020
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : December 2021

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




Primary Outcome Measures :
  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 Outcome Measures :
  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 Outcome Measures:
  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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with COVID-19 who need supplemental
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04549922


Contacts
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Contact: Fernando G Zampieri, MD +551130656611 fzampieri@hcor.com.br
Contact: Samara P Gomes +551130656611 scgomes@hcor.com.br

Locations
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Brazil
Hospital Naval Marcílio Dias Recruiting
Rio De Janeiro, Brazil
Contact: Vicente Dantas       vicentecsdantas@gmail.com   
BP-A Beneficiência Portuguesa de São Paulo Recruiting
São Paulo, Brazil
Contact: Viviane Veiga       dveiga@uol.com.br   
Hospital São Paulo - UNIFESP Recruiting
São Paulo, Brazil
Contact: Flávia R Machado       frmachado@unifesp.br   
Sponsors and Collaborators
Hospital do Coracao
Ionis Pharmaceuticals, Inc.
Hospital Moinhos de Vento
Investigators
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Principal Investigator: Fernando G Zampieri, MD Research Coordinator
Study Chair: Alexandre B Cavalcanti Institute Director
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Responsible Party: Hospital do Coracao
ClinicalTrials.gov Identifier: NCT04549922    
Other Study ID Numbers: ASKCOV_Trial
First Posted: September 16, 2020    Key Record Dates
Last Update Posted: October 27, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be available under reasonable request after approval by the steering committee.
Supporting Materials: Study Protocol
Statistical Analysis Plan (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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospital do Coracao:
antisense
kallikrein-kinin