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

Covid19 Clinical Trial

— ASKCOV  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04549922
• Other study ID #: ASKCOV_Trial
• Status: Completed
• Phase: Phase 2
• Start date: October 19, 2020
• Est. completion date: December 9, 2021

Study information

• Verified date: September 2022
• Source: Hospital do Coracao
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 111
• Est. completion date: December 9, 2021
• Est. primary completion date: December 9, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• Covid19

Intervention

Drug:
• ISIS 721744
1.2 mL of ISIS 721744 subcutaneous once after randomization
• Normal Saline
1.2 mL subcutaneous

Locations

Country	Name	City	State
Brazil	Hospital Naval Marcílio Dias	Rio De Janeiro
Brazil	BP-A Beneficiência Portuguesa de São Paulo	São Paulo
Brazil	Hospital São Paulo - UNIFESP	São Paulo

Sponsors (3)

Lead Sponsor	Collaborator
Hospital do Coracao	Hospital Moinhos de Vento, Ionis Pharmaceuticals, Inc.

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	Lymphocyte/neutrophil ratio during first 15 days after randomization	Lymphocyte/neutrophil ratio over time up to 15 or until discharge discharge day.	15 days
Other	D-dimer serum level during first 15 days after randomization	D-dimer serum levels over time or until hospital discharge.	15 days
Other	Fibrinogen serum levels during first 15 days after randomization	Fibrinogen serum levels over time up to 15 days or until hospital discharge	15 days
Other	Prothrombin Time levels during first 15 days after randomization	Prothrombin Time over time up to 15 days or until hospital discharge.	15 days
Other	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
Other	Mortality	One-year all cause mortality	1 year after randomization
Other	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
Primary	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	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
Secondary	Need for mechanical ventilation	Intubation and initiation of mechanical ventilation for any given reason	30 days (or until hospital discharge)
Secondary	Duration of mechanical ventilation	Number of days the patient remains in mechanical ventilation	30 days (or until hospital discharge)