Citicoline for Coronavirus-related Lung Injury

(SCARLET Trial)

Overseen By Sarah Karow

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ohio State University

Must not be taking: L-Dopa, Centrophenoxine, Meclofenoxate

Disqualifiers: ECMO, Hypertonia, Pregnancy, others

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether citicoline, administered through an IV, is safe and beneficial for individuals with lung problems caused by COVID-19. The researchers aim to determine if citicoline improves oxygen levels and reduces illness severity. Participants will receive either varying doses of citicoline or a placebo (a treatment with no active ingredient) for five days. Suitable candidates have experienced a COVID-19 infection within the past 10 days and require at least 4 liters of oxygen due to respiratory issues. As a Phase 1, Phase 2 trial, this research focuses on understanding citicoline's effects in people and assessing its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

You may need to stop taking certain medications, specifically those containing L-Dopa, centrophenoxine, or meclofenoxate, as they are listed in the exclusion criteria. For other medications, the protocol does not specify, so it's best to discuss with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that citicoline is generally safe for people. In one large study, only about 5% of participants experienced side effects, which were mostly mild, such as an upset stomach. When a treatment is in Phase 1 and Phase 2 trials, its safety is still under evaluation. However, citicoline's use in other conditions suggests it is usually well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard therapies for coronavirus-related lung injury, which often include oxygen therapy, corticosteroids, and antiviral medications, citicoline offers a unique approach by potentially enhancing brain function and reducing inflammation. Researchers are excited about citicoline because it is known to help stabilize cell membranes and support neurotransmitter function, which could indirectly benefit lung tissue recovery. Plus, the treatment is administered intravenously in varying doses, making it possible to tailor the dosage for optimal effect. This novel mechanism of action and delivery method distinguish citicoline from traditional treatments, and there's hope it could provide faster relief or improved outcomes.

What evidence suggests that citicoline might be an effective treatment for coronavirus-related lung injury?

Research shows that citicoline, also known as CDP-choline, might help with lung problems caused by viruses. Studies have found it can reduce lung swelling and prevent low oxygen levels in cases of viral lung damage. For example, when researchers treated mice with coronavirus using citicoline, it helped prevent low blood oxygen and reduced lung swelling. Although more research is needed, these findings suggest citicoline could potentially help with breathing and lessen lung issues related to viral infections. Participants in this trial will receive different dosages of citicoline or a placebo to evaluate its effectiveness in treating coronavirus-related lung injury. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

Adults with confirmed COVID-19 and acute respiratory failure needing oxygen therapy can join this trial. They must understand the study, not be pregnant or breastfeeding, have no allergies to citicoline, and not take certain medications like L-Dopa. Critically ill patients likely to die soon or on ECMO are excluded.

Inclusion Criteria

I can understand and agree to the study's requirements.

Adequate i.v. access available (either peripheral or central venous access)

I am admitted to OSU for severe breathing problems needing at least 4 LPM of oxygen.

Exclusion Criteria

I am currently taking medication that contains L-Dopa, centrophenoxine, or meclofenoxate.

Subjects with past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the principal investigator (PI), may pose additional risks from participation in the study or that may impact the quality or interpretation of the data obtained from the study.

I am pregnant or planning to become pregnant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive i.v. citicoline or saline twice daily for 5 consecutive days

5 days

Daily monitoring (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment until hospital discharge or up to 29 days

Up to 29 days

What Are the Treatments Tested in This Trial?

Interventions

• Supplemental Citicoline Administration

Trial Overview The SCARLET trial is testing if i.v. citicoline helps adults with severe COVID-19 breathe better compared to a saline placebo. It's double-blinded (neither doctors nor patients know who gets what), randomized (assigned by chance), and checks for safety and improvement in oxygen levels.

How Is the Trial Designed?

Group I: IV 5 mg/kg/day Citicoline Experimental Treatment 1 Intervention

i.v. bolus of 10 ml normal saline containing 5 mg/kg citicoline, administered twice daily for 5 days.

Group II: IV 10 mg/kg/day Citicoline Experimental Treatment 1 Intervention

i.v. bolus of 10 ml normal saline containing 10 mg/kg citicoline, administered twice daily for 5 days.

Group III: IV 1 mg/kg/day Citicoline Experimental Treatment 1 Intervention

i.v. bolus of 10 ml normal saline containing citicoline 1 mg/kg, administered twice daily for 5 days.

Group IV: IV 10 ml normal saline Placebo Group 1 Intervention

i.v. bolus of 10 ml normal saline (without active ingredient) administered i.v., twice daily for 5 days.

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Published Research Related to This Trial

A systematic review of 11 clinical studies involving 2771 patients found that citicoline significantly increases the rate of independence in individuals with traumatic brain injury (TBI), with a relative risk of 1.18.

The analysis showed no significant effects on mortality or safety concerns related to citicoline, suggesting it is a safe treatment option for TBI when administered in the acute phase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citicoline for the Management of Patients with Traumatic Brain Injury in the Acute Phase: A Systematic Review and Meta-Analysis. Secades, JJ., Trimmel, H., Salazar, B., et al.[2023]

Citicoline is currently approved in Europe and Japan for treating stroke and other neurological disorders, and is undergoing phase II/III trials in the U.S., indicating its potential as a therapeutic option.

The mechanism of action for citicoline involves providing essential substrates for neuronal membrane repair and enhancing acetylcholine synthesis, which may help in recovery from stroke and reduce toxicity from ischemic damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. D'Orlando, KJ., Sandage, BW.[2019]

Citicolin shows potential benefits in pulmonology, including preventing acute respiratory distress syndrome in neonates and improving chronic respiratory insufficiency.

It may also enhance respiratory mechanics in conditions with hyperelastic lungs and aid in recovering gas exchange in the alveolo-capillary barrier, suggesting a multifaceted role in respiratory therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The place of citicolin in pulmonological therapy (author's transl)]. Cornia, G., Gramiccioni, E.[2013]

The study assessed the acute toxicity of a single dose of CDP-choline (citicoline) in mice and rats, determining the lethal dose (LD50) values to understand its safety profile.

Different administration routes were evaluated, providing insights into how the method of delivery may affect the toxicity of CDP-choline, which is important for its therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDP-choline: acute toxicity study. Grau, T., Romero, A., Sacristán, A., et al.[2013]

Citicoline may help manage cognitive decline and neurological complications related to COVID-19 due to its properties that support brain cell structure and function, as well as its anti-inflammatory and neuroprotective effects.

The review suggests that citicoline could serve as an adjunctive therapy for post-COVID-19 cognitive issues, highlighting the need for future clinical trials to explore its efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Citicoline and COVID-19-Related Cognitive and Other Neurologic Complications. Turana, Y., Nathaniel, M., Shen, R., et al.[2022]

Citicoline shows potential clinical benefits for elderly patients with cognitive deficits and early-stage Alzheimer's disease, acting as a choline donor that supports the production of acetylcholine and neuronal membrane components.

Research indicates that citicoline has cholinergic and neuroprotective effects, which may help improve neuronal membrane integrity and functionality, although its efficacy in stroke patients remains inconclusive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature. Conant, R., Schauss, AG.[2013]

Intracerebroventricular administration of CDP-choline significantly increases blood pressure in both normotensive and hypotensive rats, with the effect being dose- and time-dependent, indicating its potential as a treatment for hypotension.

The pressor effect of CDP-choline is mediated through the activation of nicotinic and muscarinic cholinergic receptors, as well as increased levels of plasma vasopressin and adrenaline, highlighting its mechanism of action in reversing hypotension during hemorrhagic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular effects of intracerebroventricularly injected CDP-choline in normotensive and hypotensive animals: the involvement of cholinergic system. Savci, V., Cavun, S., Goktalay, G., et al.[2014]

In a study involving 72 Wistar rats exposed to chronic hypoxia for 6 months, those treated with CDP-choline showed significantly less severe pathological symptoms and a longer survival time compared to untreated rats.

CDP-choline demonstrated a life-prolonging effect under extreme hypoxic conditions, suggesting its potential as a protective intervention in low-oxygen environments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increase of survival time in experimental hypoxia by cytidine diphosphate choline. Hamdorf, G., Cervós-Navarro, J., Müller, R.[2016]

In a study involving 2817 patients, primarily aged 60 to 80, oral CDP-choline (citicoline) significantly improved symptoms of dizziness (48.4% improvement), headaches (46.5%), and insomnia (38.6%) over treatment periods of 15 days to 2 months.

The safety profile of CDP-choline was excellent, with only 5.01% of patients experiencing side effects, mainly mild digestive issues in 3.6% of cases, indicating it is a well-tolerated treatment option for neurological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral CDP-choline. Drug surveillance study in 2817 cases. Lozano Fernández, R.[2013]

CDP-choline, provided as citicoline, plays a crucial role in cellular function by aiding in the synthesis of phospholipids necessary for membrane formation and repair, which is vital for brain health.

Citicoline has shown protective effects against ischemia and hypoxia in various animal and cellular models, suggesting its potential to enhance neuronal function and limit damage in conditions like head trauma and neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Weiss, GB.[2019]

In a study involving 12 healthy adult volunteers, CDP-choline (citicoline) was administered in two different doses (600 mg and 1 g per day) over 5 days, showing that it is generally well-tolerated with minimal side effects.

The only reported adverse effects were transient headaches in a few participants, indicating that CDP-choline has a favorable safety profile compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDP-choline: repeated oral dose tolerance studies in adult healthy volunteers. Dinsdale, JR., Griffiths, GK., Castelló, J., et al.[2013]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38760804/

SCARLET (Supplemental Citicoline Administration to Reduce ... We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05881135

Supplemental Citicoline Administration to Reduce Lung ... The goal of this single center, double-blinded, placebo-controlled, and randomized Phase 1 trial is to determine if iv citicoline is safe and efficacious.

3. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-024-08155-0

SCARLET (Supplemental Citicoline Administration to Reduce ... In support of this, we have shown that CDP-choline strongly attenuates IAV-induced ARDS and pulmonary inflammation [58] and prevents hypoxemia ...

4. reporter.nih.gov reporter.nih.gov/search/14E9CE024F8FC5D27598B8961CAA4A01A2FFCEB861BF/project-details/10819512

RePORT RePORTER In addition, treatment of SARS CoV-2- infected K18-hACE2-transgenic mice with CDP-choline prevents development of hypoxemia and attenuates lung inflammation.

5. withpower.com withpower.com/trial/phase-2-lung-injury-4-2023-60e1f

Citicoline for Coronavirus-related Lung Injury In a study involving 2817 patients, primarily aged 60 to 80, oral CDP-choline (citicoline) significantly improved symptoms of dizziness (48.4% improvement), ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11102211/

SCARLET (Supplemental Citicoline Administration to Reduce ... We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with ...