Defibrotide for COVID-19

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must not be taking: Thrombolytic therapy

Disqualifiers: Acute bleeding, Hemodynamic instability, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

42 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this study is to evaluate the safety and feasibility of defibrotide in COVID-19 pneumonia.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use thrombolytic therapy like t-PA while participating.

What data supports the idea that Defibrotide for COVID-19 is an effective treatment?

The available research does not provide any data supporting the effectiveness of Defibrotide for treating COVID-19. Instead, the studies focus on other treatments like DAS181, Plitidepsin, and Remdesivir. Plitidepsin showed promising results in reducing viral load and improving patient outcomes, while Remdesivir is noted for its antiviral activity against COVID-19. There is no mention of Defibrotide in the context of COVID-19 treatment in the provided information. ^{1 2 3 4 5}

What safety data is available for Defibrotide treatment?

The provided research does not contain any safety data for Defibrotide or its other names such as Defitelio, Dasovas, Noravid, Prociclide, or Defibrotide sodium. The studies mentioned focus on other drugs like tocainide, procainamide, encainide, and dofetilide, which are unrelated to Defibrotide. ^{6 7 8 9 10}

Is Defibrotide a promising drug for COVID-19?

The provided research articles do not mention Defibrotide or its potential as a treatment for COVID-19. They focus on other drugs like Remdesivir and its related compounds. Therefore, based on this information, we cannot determine if Defibrotide is a promising drug for COVID-19. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for adults over 18 with severe COVID-19, showing lung complications on X-rays. They must expect to live at least another day and be able to consent. People already on blood thinners or certain therapies like ECMO or CRRT can join specific groups unless they're bleeding or unstable due to low blood pressure.

Inclusion Criteria

I am 18 years old or older.

You currently have a confirmed case of COVID-19.

I am on a blood thinner for a clot and have had no bleeding after 24 hours.

Exclusion Criteria

Pregnant or lactating

You have a known allergy or hypersensitivity to DF (the specific substance or medication).

I am currently using medication to dissolve blood clots.

Treatment Details

Interventions

• Defibrotide

Trial Overview The study tests the safety and effectiveness of a drug called Defibrotide in treating pneumonia caused by COVID-19. It aims to see if this treatment can help patients with serious symptoms.

Participant Groups

Group I: Defibrotide Experimental Treatment 1 Intervention

Defibrotide IV

Defibrotide is already approved in United States, European Union for the following indications:

Approved in United States as Defitelio for:

• Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)

Approved in European Union as Defitelio for:

• Severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Jazz Pharmaceuticals

Industry Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Findings from Research

A 10-month-old girl with respiratory distress due to COVID-19 was successfully treated with the investigational drug DAS181, which was well tolerated with minimal side effects.

The patient's respiratory distress and positive COVID-19 viral test quickly improved after starting DAS181 therapy, indicating its potential efficacy in treating severe respiratory symptoms associated with the virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Treatment of Infant With COVID-19 With the Sialidase Fusion Protein, DAS181. Danziger-Isakov, L., Khalil, N., Divanovic, A., et al.[2023]

Plitidepsin, a marine-derived cyclic peptide, effectively inhibits SARS-CoV-2 replication in hospitalized COVID-19 patients, showing a significant mean viral load reduction of 4.2 log10 by Day 15 across 45 participants.

The treatment was well tolerated with minimal adverse effects, and discharge rates improved significantly, indicating a positive impact on patient outcomes in a dose-dependent manner.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization. Varona, JF., Landete, P., Lopez-Martin, JA., et al.[2023]

Plitidepsin, a marine-derived drug, effectively inhibits SARS-CoV-2 replication at very low concentrations and shows preferential distribution to the lungs, making it a promising treatment for COVID-19.

In a study involving 46 hospitalized patients, plitidepsin demonstrated a favorable safety profile with manageable side effects, and it achieved significant reductions in viral load over time, indicating its potential efficacy in treating COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19. Varona, JF., Landete, P., Lopez-Martin, JA., et al.[2023]

In a study of 59 Japanese patients with COVID-19 pneumonia, a GS-441524 trough concentration of 70 ng/mL or higher was linked to improved symptoms, as measured by the NIAID-OS scale.

Factors such as lower estimated glomerular filtration rate (eGFR) and a body mass index (BMI) of 25 kg/m2 or more were associated with achieving the effective GS-441524 concentration, indicating that these patient characteristics may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploration of the optimal GS-441524 trough concentration for treating COVID-19. Nakano, Y., Inokuchi, Y., Hayama, T., et al.[2023]

In a Phase 3 study involving 562 participants, remdesivir (RDV) treatment was associated with accelerated improvement in several inflammation-related biomarkers, indicating its potential to enhance clinical outcomes in hospitalized COVID-19 patients.

Participants treated with RDV showed significant reductions in biomarkers like soluble angiopoietin-2 and D-dimer, along with increased lymphocyte counts, suggesting that RDV may help mitigate severe COVID-19 symptoms more effectively than placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remdesivir improves biomarkers associated with disease severity in COVID-19 patients treated in an outpatient setting. Pan, DZ., Odorizzi, PM., Schoenichen, A., et al.[2023]

In a safety evaluation of tocainide involving 369 patients with life-threatening ventricular arrhythmias, the drug was found to have a favorable risk-benefit ratio, with adverse effects primarily being transient neurological and gastrointestinal issues.

Despite some patients experiencing side effects leading to discontinuation (16%), there was no evidence of permanent organ injury, and routine lab tests showed no significant abnormalities, indicating tocainide's overall safety in emergency use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of tocainide in the American Emergency Use Program. Horn, HR., Hadidian, Z., Johnson, JL., et al.[2019]

In a study of 64 patients with recent-onset atrial fibrillation, intravenous procainamide achieved a cardioversion rate of 60.9%, allowing many patients to be discharged from the emergency department instead of being admitted to the hospital.

The most common side effect was transient hypotension, occurring in 9.4% of patients, indicating that while procainamide is effective, monitoring for this complication is important during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementation of a Procainamide-Based Cardioversion Strategy for the Management of Recent-Onset Atrial Fibrillation. Matuskowitz, AJ., Weant, KA., Gregory, H., et al.[2021]

In a review of 349 patients treated with encainide for supraventricular arrhythmias, there were no new cases of heart failure reported, even among patients with a history of heart conditions, indicating a strong safety profile.

The incidence of proarrhythmia was low at 1.4%, and the most common side effects included dizziness and nausea, with only 6% of patients discontinuing treatment due to adverse effects, suggesting encainide is generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety considerations and dosing guidelines for encainide in supraventricular arrhythmias. Soyka, LF.[2019]

In a study of 122 patients, dofetilide and propafenone were found to be equally effective in preventing episodes of paroxysmal supraventricular tachycardia (PSVT), with 50% and 54% of patients remaining free of episodes, respectively, compared to only 6% in the placebo group after 6 months.

Dofetilide was well tolerated with no instances of proarrhythmia, while propafenone caused serious adverse effects in three patients, highlighting dofetilide as a potentially safer alternative for PSVT treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo. Tendera, M., Wnuk-Wojnar, AM., Kulakowski, P., et al.[2016]

Procainamide is a widely used antiarrhythmic medication effective for preventing recurrent ventricular tachycardia and treating various supraventricular tachycardias, including atrial flutter and atrial fibrillation.

Long-term use of procainamide can lead to significant side effects, such as lupus-like syndrome and gastrointestinal issues, necessitating careful monitoring of patients, especially regarding their QT interval to prevent toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Procainamide: a perspective on its value and danger. Ellenbogen, KA., Wood, MA., Stambler, BS.[2013]

Remdesivir (RDV) is currently the only FDA-approved drug for COVID-19, but it has low stability for oral use, making it less suitable as an oral antiviral.

In contrast, GS-441524, a metabolite of RDV, shows excellent stability and a favorable oral bioavailability of 57% in mice, indicating its potential as an effective oral treatment for COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment. Xie, J., Wang, Z.[2021]

ODBG-P-RVn, an orally available prodrug of remdesivir, demonstrated 20-fold greater antiviral activity than its parent compound GS-441524 against SARS-CoV-2 and other viruses of public health concern.

The antiviral effectiveness of ODBG-P-RVn was found to be nearly equivalent to that of remdesivir in human small airway epithelial cells, suggesting it could be a promising alternative for treating COVID-19 and warrants further in vivo studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524). Lo, MK., Shrivastava-Ranjan, P., Chatterjee, P., et al.[2022]

Remdesivir is more potent and has better intracellular metabolism compared to GS-441524 in most cell types tested, indicating it may be the more effective treatment for COVID-19.

The study involved various cell lines, including Vero E6 and Calu-3, to assess the anti-SARS-CoV-2 activity of both compounds, highlighting the importance of cellular context in evaluating antiviral efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of anti-SARS-CoV-2 activity and intracellular metabolism of remdesivir and its parent nucleoside. Tao, S., Zandi, K., Bassit, L., et al.[2021]

In a study of 159 hospitalized COVID-19 patients treated with remdesivir, 141 patients recovered, indicating its efficacy in improving clinical outcomes.

Patients receiving remdesivir had a significantly lower case fatality ratio of 11.32% compared to 32.89% in those who did not receive the treatment, suggesting that remdesivir reduces mortality and shortens hospital stays.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The utility of remdesivir in SARS-CoV-2: A single tertiary care center experience from a developing country. Malik, MI., Zafar, SAF., Malik, M., et al.[2022]

The new remdesivir analogue MMT5-14 demonstrated 2- to 7-fold higher antiviral activity against various SARS-CoV-2 variants compared to remdesivir, indicating its potential as a more effective treatment for severe COVID-19.

MMT5-14 significantly improved drug delivery, with a 200- to 300-fold increase in prodrug concentration in plasma and lungs, and a 5-fold enhancement in the accumulation of its active form in lung cells, suggesting better efficacy in targeting the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of the Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV-2 Activity. Hu, H., Mady Traore, MD., Li, R., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Novel Treatment of Infant With COVID-19 With the Sialidase Fusion Protein, DAS181. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Exploration of the optimal GS-441524 trough concentration for treating COVID-19. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Remdesivir improves biomarkers associated with disease severity in COVID-19 patients treated in an outpatient setting. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Safety evaluation of tocainide in the American Emergency Use Program. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Implementation of a Procainamide-Based Cardioversion Strategy for the Management of Recent-Onset Atrial Fibrillation. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Safety considerations and dosing guidelines for encainide in supraventricular arrhythmias. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo. [2016]

10. United States pubmed.ncbi.nlm.nih.gov

Procainamide: a perspective on its value and danger. [2013]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Broad-spectrum in vitro antiviral activity of ODBG-P-RVn: an orally-available, lipid-modified monophosphate prodrug of remdesivir parent nucleoside (GS-441524). [2022]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of anti-SARS-CoV-2 activity and intracellular metabolism of remdesivir and its parent nucleoside. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

The utility of remdesivir in SARS-CoV-2: A single tertiary care center experience from a developing country. [2022]

15. United States pubmed.ncbi.nlm.nih.gov

Optimization of the Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV-2 Activity. [2023]