Covid19Phase 2ASKCOVNCT04549922
Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19
A Phase 2 study testing ISIS 721744 and Normal Saline in people with Covid19, run by Hospital do Coracao at 3 sites in Brazil.
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Covid19
- What is being tested?
- ISIS 721744 and Normal Saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 111 participants
- Where
- 3 sitesBrazil
- Study dates
- 19 Oct 2020to 9 Dec 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Who cannot join
- 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)
Show all 10Show fewer
- 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
Trial locations and contacts
3 sites in 1 country.
Brazil3 sites
Hospital Naval Marcílio Dias
Rio de Janeiro
BP-A Beneficiência Portuguesa de São Paulo
São Paulo
Hospital São Paulo - UNIFESP
São Paulo
About this study
Official title: Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial
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.
Read the 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).
- Conditions
- Covid19
- Being tested
- ISIS 721744, Normal Saline
- Keywords
- antisense, kallikrein-kinin
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ISIS 721744Drug
1.2 mL of ISIS 721744 subcutaneous once after randomization
Normal SalineDrug
1.2 mL subcutaneous
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | 1.2 mL Normal Saline, single dose subcutaneous, after randomization Receives: Drug: Normal Saline |
| ISIS 721744 | Active comparator | 1.2 mL ISIS 721744, single dose subcutaneous, after randomization Receives: Drug: ISIS 721744 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 15 days
Secondary outcomes (3)
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.
Measured: 15 days
Need for mechanical ventilation
Intubation and initiation of mechanical ventilation for any given reason
Measured: 30 days (or until hospital discharge)
Duration of mechanical ventilation
Number of days the patient remains in mechanical ventilation
Measured: 30 days (or until hospital discharge)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2020
- Study start19 Oct 2020
- Primary completion9 Dec 2020
- Study completion9 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Covid19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 111 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hospital do Coracao
- Sponsor type
- University, hospital or other
- Collaborators
- Ionis Pharmaceuticals, Inc., Hospital Moinhos de Vento
- Responsible party
- Sponsor
- Investigators
- Fernando G Zampieri, MD, Principal investigator, Research CoordinatorAlexandre B Cavalcanti, Study chair, Institute Director
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04549922
- Sponsor's protocol ID
- ASKCOV_Trial
- Acronym
- ASKCOV
- Status last verified
- Sep 2022
- First submitted
- 9 Sep 2020
- Last updated
- 22 Sep 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be available under reasonable request after approval by the steering committee.
Publications
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.
PubMed 39096659
Study at a glance
From the registry record, last updated by the sponsor on 22 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Antisense Therapy to Block the Kallikrein-kinin Pathway in COVID-19: A Phase II Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT04549922
- Acronym / sponsor ID
- ASKCOV / ASKCOV_Trial
- Conditions
- Covid19
- Keywords
- antisense, kallikrein-kinin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 111 participants (actual)
- Lead sponsor
- Hospital do CoracaoUniversity, hospital or other
- Collaborators
- Ionis Pharmaceuticals, Inc., Hospital Moinhos de Vento
- Study start
- 19 Oct 2020 (actual)
- Primary completion
- 9 Dec 2020 (actual)
- Study completion
- 9 Dec 2021 (actual)
- First posted
- 16 Sep 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Normal Saline1.2 mL Normal Saline, single dose subcutaneous, after randomization |
| ISIS 721744 | Active comparator | Drug: ISIS 7217441.2 mL ISIS 721744, single dose subcutaneous, after randomization |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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).
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ISIS 7217441.2 mL of ISIS 721744 subcutaneous once after randomization | Drug | ISIS 721744 |
| Normal Saline1.2 mL subcutaneous | Drug | Placebo |
Primary outcome
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
3 secondary outcomes
SOFA - Sequential Organ Failure Assessment Score up to 15 days after randomization
Time frame: 15 days
Need for mechanical ventilation
Time frame: 30 days (or until hospital discharge)
Duration of mechanical ventilation
Time frame: 30 days (or until hospital discharge)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Sep 2022.
- Derived from this study: PubMed 39096659Zampieri 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.
- Individual participant dataSharing planned: Yes. Data will be available under reasonable request after approval by the steering committee.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fernando G Zampieri, MD principal investigator
Research Coordinator
Alexandre B Cavalcanti study chair
Institute Director
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ISIS 721744 and Normal Saline in people with Covid19, run by Hospital do Coracao at 3 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Days alive without respiratory support (any supplemental oxygen) after 15 days (DAFOR15) (time frame: 15 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04549922, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2022.