Acute Hypoxemic Respiratory FailurePhase 2NCT04570384
Intravenous L-Citrulline Influence on the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19
A Phase 2 study testing L-Citrulline in people with Acute Hypoxemic Respiratory Failure, run by Asklepion Pharmaceuticals, LLC at 1 site in United States.
Trial summary
Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients with COVID-19 (SARS-CoV2) Illness. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Acute Hypoxemic Respiratory Failure
- What is being tested?
- L-Citrulline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 65 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Oct 2020to 30 Sep 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18-65 years.
- Clinical evidence of COVID-19 (SARS-CoV2) infection, defined as a positive COVID-19 laboratory test plus evidence of an acute hypoxemic respiratory illness requiring oxygen.
- Admitted and transferred to floor without intubation.
Who cannot join
- No consent/inability to obtain consent
- Patient, surrogate, or physician not committed to full support
- Malignant or other irreversible condition and estimated 28-day mortality ≥ 50%
- Moribund patient not expected to survive 48 hours (as defined by primary medical team) from start of study infusion
- End-stage Liver Disease as defined by Child-Pugh Score > 9
- Currently enrolled in, or participated in another study of an investigational compound within the last 30 days
Show all 10Show fewer
- Pregnant female, or female who is breast feeding
- Allergy to L-citrulline or arginine or any citrulline- or arginine-containing product
- Patient not otherwise suitable for the study in the opinion of any of the investigators
- Requirement for intubation and invasive mechanical ventilation before study enrollment
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
About this study
Official title: Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19 (SARS-CoV-2) Illness
Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients with COVID-19 (SARS-CoV2) Illness. To evaluate safety and efficacy of a bolus loading dose and continuous intravenous infusion of L-Citrulline compared to placebo in patients hospitalized with COVID-19 infection (SARS-CoV-2).
Read the detailed description
Intravenous L-citrulline (Turnobi) administration will safely restore the homeostasis of nitric oxide synthase by increasing both plasma citrulline and arginine levels. Investigators also reason that restoration of citrulline/arginine balance through citrulline administration will safely re-establish homeostasis of NOS, lower oxidative stress, and reduce inflammation, thereby delaying and potentially preventing the need for invasive mechanical ventilation in participants hospitalized with COVID-19 infection (SARS-CoV-2). The body lives in a delicate balance of homeostasis. The urea/NO cycle plays a critical role in maintaining redox homeostasis and as such, also plays a role in regulating inflammation. The biochemical relationships are complex and depend on inter-organ transfer, membrane transport, and intracellular compartmentation. However, data above demonstrate that citrulline, arginine, and NO are critical in maintaining this homeostasis through their regulation of NOS. Inflammation, especially from infection, results in decreased activity of CPS1 and increased activity of arginase, which decreases levels of both citrulline and arginine. These decreased levels result in dysregulated and uncoupled NOS, which drives both overexuberant NO production and formation of ROS. Both the NO production and ROS further exacerbate the inflammatory cascade, resulting in other organ dysfunctions, including acute lung injury. Both inflammation and oxidative stress have been shown to be driving forces for the development of ALI and regulated NOS function is vital to reducing both. Both plasma citrulline and arginine are deficient in sepsis and levels are inversely associated with development of ALI. Furthermore, citrulline replacement safely increases plasma levels of both citrulline and arginine in healthy volunteers, BMT patients, adults with sepsis, children with sickle cell disease, and children after congenital heart surgery. It seems highly likely that citrulline therapy in the setting of COVID-19 (SARS-CoV2) induced acute hypoxemic respiratory illness will safely increase citrulline and arginine levels and help re-establish NOS homeostasis, resulting in NO production in compartments that are more homeostatically appropriate so as to reduce pulmonary vascular resistance and enhance coupling of NOS to minimize superoxide production thus reducing free radical mediated ALI.
- Conditions
- Acute Hypoxemic Respiratory Failure
- Being tested
- L-Citrulline, Placebo
- Medical subject headings
- Respiratory Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-CitrullineDrug
Also called L-CIT, CIT
L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.
PlaceboDrug
Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
| Study group | Role | What they receive |
|---|---|---|
| IV L-Citrulline (Turnobi) Arm | Active comparator | Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Receives: Drug: L-Citrulline |
| Placebo Arm | Placebo comparator | Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Non-invasive/Invasive Mechanical Ventilation
Time in hours from the initiation of the treatment until mechanical ventilation is required, whether non-invasive (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) or invasive (i.e., requiring intubation).
Measured: From the start of infusion to Day 60 Follow-up
Time to Non-invasive Mechanical Ventilation
Time in hours from the initiation of the treatment until non-invasive mechanical ventilation is required (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) .
Measured: From the start of infusion to Day 60 Follow-up
Time to Invasive Mechanical Ventilation
Time in hours from the initiation of the treatment until intubation for invasive mechanical ventilation is required.
Measured: From the start of infusion to Day 60 Follow-up
Systolic Blood Pressure
Systolic blood pressure measured in mmHg
Measured: Day 1
Diastolic Blood Pressure
Diastolic blood pressure measured in mmHg
Measured: Day 1
Mean Arterial Pressure
Mean arterial pressure measured in mmHg
Measured: Day 1
Secondary outcomes (9)
Blood Levels of Arginine
Plasma levels of arginine
Measured: Plasma levels of arginine at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
Blood Levels of Citrulline
Plasma levels of citrulline
Measured: Plasma levels of citrulline at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
Evaluate the Effect of Intravenous L-Citrulline Compared to Placebo as Measured by the Total Length of All Mechanical Ventilation
Total length of time of any mechanical ventilation
Measured: Day 1 through Day 60 Follow Up
Evaluate the Effect of IV L-Citrulline to Placebo for Hospital All Cause Mortality
To evaluate the effect of intravenous L-Citrulline compared to placebo on Hospital all-cause mortality
Measured: Day 1 through day 12
Percentage of Patients Admitted to Intensive Care
Measured: Day 1 through Day 12 (DC)
Duration of Intensive Care Unit (ICU) Stay
Length of ICU stay (days)
Measured: From admission to ICU until discharge or death
Duration of Hospitalisation
Length of hospital stay (days)
Measured: From admission to hospital until discharge or death
Number of Patients Requiring Intubation
Percentage of patients requiring any mechanical ventilation, invasive mechanical ventilation and non-invasive mechanical ventilation.
Measured: From the start of infusion to Day 60 Follow-up
Overall Duration of Mechanical Ventilation
Total time on any mechanical ventilation, invasive mechanical ventilation, non-invasive mechanical ventilation and nasal cannula
Measured: From the start of infusion to Day 60 Follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Sep 2020
- Study start15 Oct 2020
- Primary completion30 Aug 2021
- Study completion30 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acute Hypoxemic Respiratory FailureStudies 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
- Model description
- Placebo controlled and Active Drug
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- Asklepion Pharmaceuticals, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Gurdyal Kalsi, MD, MFPM, Study director, Asklepion Pharmaceuticals, LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04570384
- Sponsor's protocol ID
- CIT-COVID19-002-01
- Status last verified
- Jan 2023
- First submitted
- 17 Sep 2020
- Last updated
- 22 Feb 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19 (SARS-CoV-2) Illness
- ClinicalTrials.gov ID
- NCT04570384
- Acronym / sponsor ID
- CIT-COVID19-002-01
- Conditions
- Acute Hypoxemic Respiratory Failure
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- Asklepion Pharmaceuticals, LLCIndustry (pharma, biotech, devices)
- Study start
- 15 Oct 2020 (actual)
- Primary completion
- 30 Aug 2021 (actual)
- Study completion
- 30 Sep 2021 (actual)
- First posted
- 30 Sep 2020 (actual)
- Results
- Posted 22 Feb 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients with COVID-19 (SARS-CoV2) Illness. To evaluate safety and efficacy of a bolus loading dose and continuous intravenous infusion of L-Citrulline compared to placebo in patients hospitalized with COVID-19 infection (SARS-CoV-2).
Detailed description
Intravenous L-citrulline (Turnobi) administration will safely restore the homeostasis of nitric oxide synthase by increasing both plasma citrulline and arginine levels. Investigators also reason that restoration of citrulline/arginine balance through citrulline administration will safely re-establish homeostasis of NOS, lower oxidative stress, and reduce inflammation, thereby delaying and potentially preventing the need for invasive mechanical ventilation in participants hospitalized with COVID-19 infection (SARS-CoV-2). The body lives in a delicate balance of homeostasis. The urea/NO cycle plays a critical role in maintaining redox homeostasis and as such, also plays a role in regulating inflammation. The biochemical relationships are complex and depend on inter-organ transfer, membrane transport, and intracellular compartmentation. However, data above demonstrate that citrulline, arginine, and NO are critical in maintaining this homeostasis through their regulation of NOS. Inflammation, especially from infection, results in decreased activity of CPS1 and increased activity of arginase, which decreases levels of both citrulline and arginine. These decreased levels result in dysregulated and uncoupled NOS, which drives both overexuberant NO production and formation of ROS. Both the NO production and ROS further exacerbate the inflammatory cascade, resulting in other organ dysfunctions, including acute lung injury. Both inflammation and oxidative stress have been shown to be driving forces for the development of ALI and regulated NOS function is vital to reducing both. Both plasma citrulline and arginine are deficient in sepsis and levels are inversely associated with development of ALI. Furthermore, citrulline replacement safely increases plasma levels of both citrulline and arginine in healthy volunteers, BMT patients, adults with sepsis, children with sickle cell disease, and children after congenital heart surgery. It seems highly likely that citrulline therapy in the setting of COVID-19 (SARS-CoV2) induced acute hypoxemic respiratory illness will safely increase citrulline and arginine levels and help re-establish NOS homeostasis, resulting in NO production in compartments that are more homeostatically appropriate so as to reduce pulmonary vascular resistance and enhance coupling of NOS to minimize superoxide production thus reducing free radical mediated ALI.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Placebo controlled and Active Drug
| Arm | Type | Receives |
|---|---|---|
| IV L-Citrulline (Turnobi) Arm | Active comparator | Drug: L-CitrullinePatients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. |
| Placebo Arm | Placebo comparator | Drug: PlaceboPatients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Age 18-65 years.
- Clinical evidence of COVID-19 (SARS-CoV2) infection, defined as a positive COVID-19 laboratory test plus evidence of an acute hypoxemic respiratory illness requiring oxygen.
- Admitted and transferred to floor without intubation.
Key exclusion criteria (10 listed)
- No consent/inability to obtain consent
- Patient, surrogate, or physician not committed to full support
- Malignant or other irreversible condition and estimated 28-day mortality ≥ 50%
- Moribund patient not expected to survive 48 hours (as defined by primary medical team) from start of study infusion
- End-stage Liver Disease as defined by Child-Pugh Score > 9
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 |
|---|---|---|
| L-CitrullineAlso: L-CIT, CITL-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days. | Drug | IV L-Citrulline (Turnobi) Arm |
| PlaceboPatients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days. | Drug | Placebo Arm |
Primary outcome
Time to Non-invasive/Invasive Mechanical Ventilation
Time frame: From the start of infusion to Day 60 Follow-up
Time in hours from the initiation of the treatment until mechanical ventilation is required, whether non-invasive (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) or invasive (i.e., requiring intubation).
Time to Non-invasive Mechanical Ventilation
Time frame: From the start of infusion to Day 60 Follow-up
Time in hours from the initiation of the treatment until non-invasive mechanical ventilation is required (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) .
Time to Invasive Mechanical Ventilation
Time frame: From the start of infusion to Day 60 Follow-up
Time in hours from the initiation of the treatment until intubation for invasive mechanical ventilation is required.
Systolic Blood Pressure
Time frame: Day 1
Systolic blood pressure measured in mmHg
Diastolic Blood Pressure
Time frame: Day 1
Diastolic blood pressure measured in mmHg
Mean Arterial Pressure
Time frame: Day 1
Mean arterial pressure measured in mmHg
9 secondary outcomes
Blood Levels of Arginine
Time frame: Plasma levels of arginine at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
Blood Levels of Citrulline
Time frame: Plasma levels of citrulline at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
Evaluate the Effect of Intravenous L-Citrulline Compared to Placebo as Measured by the Total Length of All Mechanical Ventilation
Time frame: Day 1 through Day 60 Follow Up
Evaluate the Effect of IV L-Citrulline to Placebo for Hospital All Cause Mortality
Time frame: Day 1 through day 12
Percentage of Patients Admitted to Intensive Care
Time frame: Day 1 through Day 12 (DC)
Duration of Intensive Care Unit (ICU) Stay
Time frame: From admission to ICU until discharge or death
Duration of Hospitalisation
Time frame: From admission to hospital until discharge or death
Number of Patients Requiring Intubation
Time frame: From the start of infusion to Day 60 Follow-up
Overall Duration of Mechanical Ventilation
Time frame: From the start of infusion to Day 60 Follow-up
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Feb 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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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.
Gurdyal Kalsi, MD, MFPM study director
Asklepion Pharmaceuticals, LLC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing L-Citrulline in people with Acute Hypoxemic Respiratory Failure, run by Asklepion Pharmaceuticals, LLC at 1 site in United States.
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 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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?
Yes. Results are posted in the registry (first posted 22 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Time to Non-invasive/Invasive Mechanical Ventilation (time frame: From the start of infusion to Day 60 Follow-up). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 Feb 2023.