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

Duration: Up to 21 days

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests defibrotide, a medication for severe veno-occlusive disease, to determine its safety and feasibility in treating pneumonia caused by COVID-19. The focus is on patients with COVID-19 who show lung problems in scans. Candidates include those with confirmed COVID-19 infection and noticeable lung issues on scans. The study aims to determine if defibrotide can manage these symptoms without causing harm. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that defibrotide is likely to be safe for humans?

Research is investigating the safety of defibrotide for treating COVID-19 pneumonia. The FDA has already approved defibrotide for other uses, indicating its safety profile is well-established. However, specific safety data for its use with COVID-19 is not yet available.

In other research, defibrotide has been tested for safety in serious lung conditions like ARDS (acute respiratory distress syndrome). These studies are part of ongoing efforts to assess how well individuals tolerate defibrotide in such situations. Although detailed safety data is not yet available, the existence of these studies suggests that researchers consider defibrotide a promising option.

This trial is in a middle phase, indicating that earlier studies have shown enough potential to warrant further testing. This phase primarily focuses on ensuring the treatment's safety for a larger group and determining the appropriate dose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for COVID-19?

Defibrotide is unique because, unlike typical COVID-19 treatments like antivirals or corticosteroids, it is derived from porcine intestinal mucosa and primarily used to protect blood vessels and reduce inflammation. Most COVID-19 treatments aim to directly target the virus or suppress the immune response, but Defibrotide works by enhancing the breakdown of blood clots and stabilizing endothelial cells, which line blood vessels. Researchers are excited about Defibrotide because it offers a novel approach to managing the severe inflammatory and clotting complications seen in COVID-19 patients, potentially reducing the risk of organ damage associated with the virus.

What evidence suggests that defibrotide might be an effective treatment for COVID-19 pneumonia?

Research suggests that defibrotide, the investigational treatment in this trial, might help manage severe COVID-19 complications by protecting blood vessels and reducing inflammation. Early studies have shown that defibrotide is safe and generally well-tolerated, with no major issues related to bleeding or clotting. Growing evidence indicates it could help treat severe lung conditions related to COVID-19. However, limited data exist on its effectiveness specifically for COVID-19 pneumonia. The potential of this treatment lies in its ability to address problems with blood vessel linings associated with COVID-19. ^{1 2 4 5 6}

Are You a Good Fit for This Trial?

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

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.

You are expected to live for at least 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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive defibrotide for the treatment of severe COVID-19 pneumonia

Up to 21 days

Daily administration (in-hospital)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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 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]

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]

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]

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]

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]

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]

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 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 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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04652115

Defibrotide for the Treatment of Severe COVID-19 This study is a prospective, single-arm, two-cohort, phase 2 pilot study that will evaluate the safety and efficacy of defibrotide in clinically severe COVID- ...

2. withpower.com withpower.com/trial/phase-3-covid-19-2021-27c3c

Defibrotide for COVID-19 · Recruiting Participants for Phase ... The available research does not provide any data supporting the effectiveness of Defibrotide for treating COVID-19. Instead, the studies focus on other ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8993696/

Defibrotide Therapy for SARS-CoV-2 ARDS - PubMed Central The use of defibrotide for management of SARS-CoV-2-related ARDS proved safe and tolerable. No hemorrhagic or thrombotic complications were reported during ...

4. mdpi.com mdpi.com/2218-273X/15/7/1004

Defibrotide for Protecting Against and Managing ... We also explore emerging evidence on defibrotide's potential in SARS-CoV-2 infection-associated endotheliopathies, including acute COVID-19 and post-acute ...

5. sciencedirect.com sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/defibrotide

Defibrotide - an overview | ScienceDirect Topics Results from this study, as well as findings from the other phase II clinical trial, confirm that defitelio improves survival in both pediatric and adult ...

6. fda.gov fda.gov/drugs/resources-information-approved-drugs/defitelio-defibrotide-sodium

Defitelio (defibrotide sodium) The Day +100 survival rates for Study 1, Study 2 and Study 3 were 38% (95% CI: 29%, 48%), 44% (95% CI: 33%, 55%) and 45% (95% CI: 40%, 51%) ...