Acute Respiratory Distress SyndromePhase 4NCT04335786
Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease
A Phase 4 study testing Valsartan (Diovan) in people with Acute Respiratory Distress Syndrome and SARS-CoV-2, run by Radboud University Medical Center at 7 sites in Netherlands.
Trial summary
Rationale: The current SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the so-called acute respiratory distress syndrome (ARDS). The renin-angiotensin-system (RAS) plays an important role in the development of ARDS. ACE2 is one of the enzymes involved in the RAS cascade. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Respiratory Distress Syndrome, SARS-CoV-2, COVID
- What is being tested?
- Valsartan (Diovan)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 23 participants
- Where
- 7 sitesNetherlands
- Study dates
- 17 Apr 2020to 25 May 2021
- Phase
- Phase 4
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult (age ≥ 18 years)
- Admitted to the hospital of any participating center
- Confirmed SARS-CoV-2 infection with either: positive laboratory test for SARS-CoV-2* ; or positive CT thorax diagnostic for SARS-CoV-2 infection according to the prevailing criteria
- Randomization:
- Within 24 hours of confirmed in-hospital SARS-CoV-2 infection diagnosis OR
- within 24 hours of hospital admission in case of pre-hospital confirmed SARS-CoV-2 infection.
- In case there is a lack of laboratory tests for SARS-CoV-2 in the participating center of the potentially eligible patient, a positive laboratory test for SARS-CoV-2 will be no longer required. In that case, the potentially eligible patient needs to meet the prevailing criteria for the diagnosis of SARS-CoV-2 infection of that participating center, such as typical abnormalities on pulmonary CT in the setting of high clinical suspicion of SARS-CoV-2 infection.
Who cannot join
- Admitted to ICU prior to randomization
- Currently taking an ARB or angiotensin-receptor-neprilysin-inhibitor (ARNI)
- Use of other investigational drugs at the time of enrollment
- Prior reaction or intolerance to an ARB or ARNI; or severe intolerance to an ACEi, defined as angio-oedema requiring medical intervention
- Systolic blood pressure < 105mmHg or diastolic blood pressure <65mmHg
- Potassium greater than 5.5 mEq/L within 4 weeks of study enrollment.
Show all 15Show fewer
- Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 4 weeks of study initiation
- A known history of renal artery stenosis
- AST and/or ALT > 3 times the upper limit of normal within 4 weeks of study enrollment. In case of mild to moderate liver dysfunction valsartan dosage will be limited to a maximum of 80mg
- Severe liver dysfunction, biliary cirrhosis or cholestasis
- Severe volume depletion or severe acute kidney injury that, in the opinion of the investigator, would preclude administration of valsartan
- Concurrent treatment with Aliskiren
- Inability to obtain informed consent
- Pregnancy or breastfeeding
- In females of childbearing age, unwillingness to use birth control or to be sexually abstinent for the duration of the study
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
Netherlands7 sites
Jeroen Bosch Ziekenhuis
's-Hertogenbosch
Rijnstate
Arnhem, 6815AD
Radboudumc
Nijmegen
Laurentius Ziekenhuis
Roermond
Erasmus MC
Rotterdam
Franciscus Gasthuis
Rotterdam
Ikazia Ziekenhuis
Rotterdam
About this study
Official title: PRAETORIAN-COVID: A Double-blind, Placebo-controlled Randomized Clinical Trial With Valsartan for PRevention of Acute rEspiraTORy dIstress Syndrome in hospitAlized patieNts With SARS-COV-2 (COVID-19) Infection Disease
Rationale: The current SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the so-called acute respiratory distress syndrome (ARDS). The renin-angiotensin-system (RAS) plays an important role in the development of ARDS.
ACE2 is one of the enzymes involved in the RAS cascade. Virus spike protein binds to ACE2 to form a complex suitable for cellular internalization. The downregulation of ACE2 results in the excessive accumulation of angiotensin II, and it has been demonstrated that the stimulation of the angiotensin II type 1a receptor (AT1R) increases pulmonary vascular permeability, explaining the increased lung pathology when activity of ACE2 is decreased. Currently available AT1R blockers (ARBs) such as valsartan, have the potential to block this pathological process mediated by angiotensin II. There are presently two complementary mechanisms suggested: 1) ARBs block the excessive angiotensin-mediated AT1R activation, and 2) they upregulate ACE2, which reduces angiotensin II concentrations and increases the production of the protective vasodilator angiotensin 1-7. In light of the above, ARBs may prevent the development of ARDS and avert morbidity (admission to intensive care unit (ICU) and mechanical ventilation) and mortality.
Read more
Objective: To investigate the effect of the ARB valsartan in comparison to placebo on the occurrence of one of the following items, within 14 days of randomization:1) ICU admission; 2) Mechanical ventilation; 3) Death.
Study design: A double-blind, placebo-controlled 1:1 randomized clinical trial Study population: Adult hospitalized SARS-CoV-2-infected patients (n=651). Intervention: The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160mg b.i.d. and the placebo arm will receive a matching placebo also titrated to blood pressure. Treatment duration will be 14 days or up to hospital discharge < 14 days or occurrence of the primary endpoint if < 14 days.
Main study endpoint: The primary study endpoint is the occurrence within 14 days of randomization of either: 1) ICU admission; 2) Mechanical ventilation; 3) Death.
- Conditions
- Acute Respiratory Distress Syndrome, SARS-CoV-2, COVID, COVID-19, Severe Acute Respiratory Syndrome
- Being tested
- Valsartan (Diovan), Placebo oral tablet
- Keywords
- Acute Respiratory Distress Syndrome, SARS-CoV-2, Therapeutics, Valsartan, Angiotensin Receptor Blockade, Angiotensin Receptor Blockers, ARBs, COVID-19
- Medical subject headings
- Respiratory Distress Syndrome, COVID-19, Severe Acute Respiratory Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Valsartan (Diovan)Drug
At the time of randomization each participant will start with study treatment and continue up to 14 days, or up to reaching the primary endpoint, or up to hospital discharge, or up to any of the pre-defined stopping criteria.
Study drug dosages will be titrated to blood pressure with a maximum of 160mg b.i.d.
Placebo oral tabletDrug
At the time of randomization each participant will start with study treatment and continue up to 14 days, or up to reaching the primary endpoint, or up to hospital discharge, or up to any of the pre-defined stopping criteria.
| Study group | Role | What they receive |
|---|---|---|
| Active treatment arm | Experimental | Valsartan at a dosage and frequency titrated to blood pressure with 80mg or 160mg tablets up to a maximum dose of 160mg b.i.d. Receives: Drug: Valsartan (Diovan) |
| Placebo arm | Placebo comparator | Matching 80mg or 160mg placebo tablets at a dosage and frequency titrated to systolic blood pressure Receives: Drug: Placebo oral tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
first occurrence of intensive care unit admission, mechanical ventilation or death
Death is defined as all-cause mortality
Measured: within 14 days
Secondary outcomes (4)
Death
All-cause mortality; and time to all-cause mortality
Measured: Within 14 days, 30 days, 90 days and at 1 year
Mechanical ventilation
Occurrence of mechanical ventilation and time to ventilation
Measured: within 14 days
Intensive care unit admission
Occurrence of ICU admission and time to admission
Measured: within 14 days
Occurrence of acute kidney injury
Defined as a 50% decline in estimated glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2
Measured: Within 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Apr 2020
- Study start17 Apr 2020
- Primary completion25 May 2021
- Study completion25 May 2021
Why it stopped: Enrollment was stopped to facilitate successful enrollment for the ACE2RAS-domain of the REMAP-CAP trial.
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 Acute Respiratory Distress SyndromeStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Niels van Royen, MD PhD, Study chair, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04335786
- Sponsor's protocol ID
- NL73547.091.20
- Other IDs
- 2020-001320-34
- Status last verified
- Apr 2020
- First submitted
- 2 Apr 2020
- Last updated
- 24 Sep 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Gommans DHF, Nas J, Pinto-Sietsma SJ, Koop Y, Konst RE, Mensink F, Aarts GWA, Konijnenberg LSF, Cortenbach K, Verhaert DVM, Thannhauser J, Mol JQ, Rooijakkers MJP, Vos JL, van Rumund A, Vart P, Hassing RJ, Cornel JH, de Jager CPC, van den Heuvel MM, van der Hoeven HG, Verbon A, Pinto YM, van Royen N, van Kimmenade RRJ; Event committee; de Leeuw PW, van Agtmael MA, Bresser P; Data Safety Monitoring Board; van Gilst WH, Vonk-Noordergraaf A, Tijssen JGP; Steering committee; van Royen N, de Jager CPC, van den Heuvel MM, van der Hoeven HG, Verbon A, Pinto YM, van Kimmenade RRJ. Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease. Am Heart J. 2020 Aug;226:60-68. doi: 10.1016/j.ahj.2020.05.010. Epub 2020 May 21.
PubMed 32512291
Study at a glance
From the registry record, last updated by the sponsor on 24 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PRAETORIAN-COVID: A Double-blind, Placebo-controlled Randomized Clinical Trial With Valsartan for PRevention of Acute rEspiraTORy dIstress Syndrome in hospitAlized patieNts With SARS-COV-2 (COVID-19) Infection Disease
- ClinicalTrials.gov ID
- NCT04335786
- Acronym / sponsor ID
- NL73547.091.20
- Conditions
- Acute Respiratory Distress Syndrome, SARS-CoV-2, COVID, COVID-19, Severe Acute Respiratory Syndrome
- Keywords
- Acute Respiratory Distress Syndrome, SARS-CoV-2, Therapeutics, Valsartan, Angiotensin Receptor Blockade, Angiotensin Receptor Blockers, ARBs, COVID-19
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Enrollment was stopped to facilitate successful enrollment for the ACE2RAS-domain of the REMAP-CAP trial.
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- 17 Apr 2020 (actual)
- Primary completion
- 25 May 2021 (actual)
- Study completion
- 25 May 2021 (actual)
- First posted
- 6 Apr 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.
Rationale: The current SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the so-called acute respiratory distress syndrome (ARDS). The renin-angiotensin-system (RAS) plays an important role in the development of ARDS.
ACE2 is one of the enzymes involved in the RAS cascade. Virus spike protein binds to ACE2 to form a complex suitable for cellular internalization. The downregulation of ACE2 results in the excessive accumulation of angiotensin II, and it has been demonstrated that the stimulation of the angiotensin II type 1a receptor (AT1R) increases pulmonary vascular permeability, explaining the increased lung pathology when activity of ACE2 is decreased. Currently available AT1R blockers (ARBs) such as valsartan, have the potential to block this pathological process mediated by angiotensin II. There are presently two complementary mechanisms suggested: 1) ARBs block the excessive angiotensin-mediated AT1R activation, and 2) they upregulate ACE2, which reduces angiotensin II concentrations and increases the production of the protective vasodilator angiotensin 1-7. In light of the above, ARBs may prevent the development of ARDS and avert morbidity (admission to intensive care unit (ICU) and mechanical ventilation) and mortality.
Objective: To investigate the effect of the ARB valsartan in comparison to placebo on the occurrence of one of the following items, within 14 days of randomization:1) ICU admission; 2) Mechanical ventilation; 3) Death.
Study design: A double-blind, placebo-controlled 1:1 randomized clinical trial Study population: Adult hospitalized SARS-CoV-2-infected patients (n=651). Intervention: The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160mg b.i.d. and the placebo arm will receive a matching placebo also titrated to blood pressure. Treatment duration will be 14 days or up to hospital discharge < 14 days or occurrence of the primary endpoint if < 14 days.
Main study endpoint: The primary study endpoint is the occurrence within 14 days of randomization of either: 1) ICU admission; 2) Mechanical ventilation; 3) Death.
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 |
|---|---|---|
| Active treatment arm | Experimental | Drug: Valsartan (Diovan)Valsartan at a dosage and frequency titrated to blood pressure with 80mg or 160mg tablets up to a maximum dose of 160mg b.i.d. |
| Placebo arm | Placebo comparator | Drug: Placebo oral tabletMatching 80mg or 160mg placebo tablets at a dosage and frequency titrated to systolic blood pressure |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Adult (age ≥ 18 years)
- Admitted to the hospital of any participating center
- Confirmed SARS-CoV-2 infection with either: positive laboratory test for SARS-CoV-2* ; or positive CT thorax diagnostic for SARS-CoV-2 infection according to the prevailing criteria
- Randomization:
Key exclusion criteria (15 listed)
- Admitted to ICU prior to randomization
- Currently taking an ARB or angiotensin-receptor-neprilysin-inhibitor (ARNI)
- Use of other investigational drugs at the time of enrollment
- Prior reaction or intolerance to an ARB or ARNI; or severe intolerance to an ACEi, defined as angio-oedema requiring medical intervention
- Systolic blood pressure < 105mmHg or diastolic blood pressure <65mmHg
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 |
|---|---|---|
| Valsartan (Diovan)At the time of randomization each participant will start with study treatment and continue up to 14 days, or up to reaching the primary endpoint, or up to hospital discharge, or up to any of the pre-defined stopping criteria. Study drug dosages will be titrated to blood pressure with a maximum of 160mg b.i.d. | Drug | Active treatment arm |
| Placebo oral tabletAt the time of randomization each participant will start with study treatment and continue up to 14 days, or up to reaching the primary endpoint, or up to hospital discharge, or up to any of the pre-defined stopping criteria. | Drug | Placebo arm |
Primary outcome
first occurrence of intensive care unit admission, mechanical ventilation or death
Time frame: within 14 days
Death is defined as all-cause mortality
4 secondary outcomes
Death
Time frame: Within 14 days, 30 days, 90 days and at 1 year
Mechanical ventilation
Time frame: within 14 days
Intensive care unit admission
Time frame: within 14 days
Occurrence of acute kidney injury
Time frame: Within 14 days
Results and safety
The study was stopped early (reason given: Enrollment was stopped to facilitate successful enrollment for the ACE2RAS-domain of the REMAP-CAP trial.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Sep 2021.
- Derived from this study: PubMed 32512291Gommans DHF, Nas J, Pinto-Sietsma SJ, Koop Y, Konst RE, Mensink F, Aarts GWA, Konijnenberg LSF, Cortenbach K, Verhaert DVM, Thannhauser J, Mol JQ, Rooijakkers MJP, Vos JL, van Rumund A, Vart P, Hassing RJ, Cornel JH, de Jager CPC, van den Heuvel MM, van der Hoeven HG, Verbon A, Pinto YM, van Royen N, van Kimmenade RRJ; Event committee; de Leeuw PW, van Agtmael MA, Bresser P; Data Safety Monitoring Board; van Gilst WH, Vonk-Noordergraaf A, Tijssen JGP; Steering committee; van Royen N, de Jager CPC, van den Heuvel MM, van der Hoeven HG, Verbon A, Pinto YM, van Kimmenade RRJ. Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease. Am Heart J. 2020 Aug;226:60-68. doi: 10.1016/j.ahj.2020.05.010. Epub 2020 May 21.
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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.
Niels van Royen, MD PhD study chair
Radboud University Medical Center
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Valsartan (Diovan) in people with Acute Respiratory Distress Syndrome and SARS-CoV-2, run by Radboud University Medical Center at 7 sites in Netherlands.
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 7 inclusion and 15 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: stopped early, as of the sponsor's last update on 24 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Netherlands. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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 was stopped early (reason given: Enrollment was stopped to facilitate successful enrollment for the ACE2RAS-domain of the REMAP-CAP trial.). Results are not available in the source record.
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?
first occurrence of intensive care unit admission, mechanical ventilation or death (time frame: within 14 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 NCT04335786, 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 24 Sep 2021.