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

Primary Purpose

Covid19

Status
Completed
Phase
Phase 2
Locations
Brazil
Study Type
Interventional
Intervention
ISIS 721744
Normal Saline
Sponsored by
Hospital do Coracao
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Covid19 focused on measuring antisense, kallikrein-kinin

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hospital Naval Marcílio Dias
  • BP-A Beneficiência Portuguesa de São Paulo
  • Hospital São Paulo - UNIFESP

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

ISIS 721744

Arm Description

1.2 mL Normal Saline, single dose subcutaneous, after randomization

1.2 mL ISIS 721744, single dose subcutaneous, after randomization

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
Need for mechanical ventilation
Intubation and initiation of mechanical ventilation for any given reason
Duration of mechanical ventilation
Number of days the patient remains in mechanical ventilation

Full Information

First Posted
September 9, 2020
Last Updated
September 21, 2022
Sponsor
Hospital do Coracao
Collaborators
Ionis Pharmaceuticals, Inc., Hospital Moinhos de Vento
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1. Study Identification

Unique Protocol Identification Number
NCT04549922
Brief Title
Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19
Acronym
ASKCOV
Official Title
Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
October 19, 2020 (Actual)
Primary Completion Date
December 9, 2020 (Actual)
Study Completion Date
December 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospital do Coracao
Collaborators
Ionis Pharmaceuticals, Inc., Hospital Moinhos de Vento

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid19
Keywords
antisense, kallikrein-kinin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
111 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
1.2 mL Normal Saline, single dose subcutaneous, after randomization
Arm Title
ISIS 721744
Arm Type
Active Comparator
Arm Description
1.2 mL ISIS 721744, single dose subcutaneous, after randomization
Intervention Type
Drug
Intervention Name(s)
ISIS 721744
Intervention Description
1.2 mL of ISIS 721744 subcutaneous once after randomization
Intervention Type
Drug
Intervention Name(s)
Normal Saline
Intervention Description
1.2 mL subcutaneous
Primary Outcome Measure Information:
Title
Days alive without respiratory support (any supplemental oxygen) after 15 days (DAFOR15)
Description
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
Time Frame
15 days
Secondary Outcome Measure Information:
Title
SOFA - Sequential Organ Failure Assessment Score up to 15 days after randomization
Description
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.
Time Frame
15 days
Title
Need for mechanical ventilation
Description
Intubation and initiation of mechanical ventilation for any given reason
Time Frame
30 days (or until hospital discharge)
Title
Duration of mechanical ventilation
Description
Number of days the patient remains in mechanical ventilation
Time Frame
30 days (or until hospital discharge)
Other Pre-specified Outcome Measures:
Title
Oxygenation index
Description
Daily oxygenation levels assessed using the ROX index [(Oxygen Saturation/Inspired Fraction)/Respiratory Rate] from randomization to discharge or day 14, whichever comes first.
Time Frame
14 days
Title
C-reactive protein levels during first 15 days after randomization
Description
C-reactive protein levels over time up to 15 days or hospital discharge.
Time Frame
15 days
Title
Lymphocyte/neutrophil ratio during first 15 days after randomization
Description
Lymphocyte/neutrophil ratio over time up to 15 or until discharge discharge day.
Time Frame
15 days
Title
D-dimer serum level during first 15 days after randomization
Description
D-dimer serum levels over time or until hospital discharge.
Time Frame
15 days
Title
Fibrinogen serum levels during first 15 days after randomization
Description
Fibrinogen serum levels over time up to 15 days or until hospital discharge
Time Frame
15 days
Title
Prothrombin Time levels during first 15 days after randomization
Description
Prothrombin Time over time up to 15 days or until hospital discharge.
Time Frame
15 days
Title
Activated Partial Thromboplastin Time during first 15 days after randomization
Description
Activated Partial Thromboplastin Time over time up to 15 days or until hospital discharge.
Time Frame
15 days
Title
Mortality
Description
One-year all cause mortality
Time Frame
1 year after randomization
Title
Euroquol questionnaire for quality of life with 5 dimensions (EQ-5D)
Description
Quality of Life measured by EQ-5D from 11111-33333, lower values being better
Time Frame
1 year after randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fernando G Zampieri, MD
Organizational Affiliation
Research Coordinator
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alexandre B Cavalcanti
Organizational Affiliation
Institute Director
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Naval Marcílio Dias
City
Rio De Janeiro
Country
Brazil
Facility Name
BP-A Beneficiência Portuguesa de São Paulo
City
São Paulo
Country
Brazil
Facility Name
Hospital São Paulo - UNIFESP
City
São Paulo
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

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

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