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

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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

Tracking Information
First Submitted Date  ICMJE September 9, 2020
First Posted Date  ICMJE September 16, 2020
Last Update Posted Date October 27, 2020
Estimated Study Start Date  ICMJE October 21, 2020
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 11, 2020)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 11, 2020)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 11, 2020)
  • 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.
  • 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.
  • 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.
  • D-dimer serum level during first 15 days after randomization [ Time Frame: 15 days ]
    D-dimer serum levels over time or until hospital discharge.
  • 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
  • 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.
  • 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.
  • Mortality [ Time Frame: 1 year after randomization ]
    One-year all cause mortality
  • 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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19
Official Title  ICMJE Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial
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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Covid19
Intervention  ICMJE
  • Drug: ISIS 721744
    1.2 mL of ISIS 721744 subcutaneous once after randomization
  • Drug: Normal Saline
    1.2 mL subcutaneous
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    1.2 mL Normal Saline, single dose subcutaneous, after randomization
    Intervention: Drug: Normal Saline
  • Active Comparator: ISIS 721744
    1.2 mL ISIS 721744, single dose subcutaneous, after randomization
    Intervention: Drug: ISIS 721744
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 23, 2020)
110
Original Estimated Enrollment  ICMJE
 (submitted: September 11, 2020)
90
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Fernando G Zampieri, MD +551130656611 fzampieri@hcor.com.br
Contact: Samara P Gomes +551130656611 scgomes@hcor.com.br
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04549922
Other Study ID Numbers  ICMJE ASKCOV_Trial
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be available under reasonable request after approval by the steering committee.
Supporting Materials: Study Protocol
Supporting Materials: 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
Responsible Party Hospital do Coracao
Study Sponsor  ICMJE Hospital do Coracao
Collaborators  ICMJE
  • Ionis Pharmaceuticals, Inc.
  • Hospital Moinhos de Vento
Investigators  ICMJE
Principal Investigator: Fernando G Zampieri, MD Research Coordinator
Study Chair: Alexandre B Cavalcanti Institute Director
PRS Account Hospital do Coracao
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP