Clinical trial to test the efficacy of defibrotide medicine for reducing COVID-19 death rate

The Neurosciences Institute, mixed centre of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) of Elche, have collaborated on the first clinical trial conducted in the world to test whether the defibrotide (DEF) medicine, which has already been authorized to treat a severe obstruction of the hepatic sinusoidal veins of people who have undergone a bone marrow transplant, can be used as therapy against COVID-19.

The work group of Experimental Embryology of the Neurosciences Institute, belonging to the Spanish Network of Cell Therapy (TerCel), is working on the development of experiments that will help study the effects that defibrotide has on the endothelium cells of the blood capillaries of the lung, and then on the cells of the alveoli of the lungs.

The trial is being coordinated by the Hospital Clínico Unviersitario Virgen de la Arrixaca (HCUVA) and the Murcia Institute of Biosanitary Research (IMIB).

The Hematopoietic Transplant and Cell Therapy group of the IMIB, which is directed by Doctor José María Moraleda, presented this proposal recently for the urgent call of the COVID-19 fund, launched by the Carlos III Health Institute (ISCIII) for the scientific and technological fight against the coronavirus pandemic.

The ISCIII has communicated to the IMIB the favourable resolution to the clinical study proposed by Doctor Moraleda, in collaboration with a comprehensive multidisciplinary team of clinicians and researchers of the Hospital Clínico Universitario Virgen de la Arrixaca, and TerCel, awarding it €115,000.

The ISCIII considers that "the funded proposal is appropriate for the emergency situation, allowing for an immediate implementation and launching in the National Healthcare System, with results that are specific, fast and suited to the current situation."

Authorization from the Spanish Agency of Medicines

As is mandatory in this type of studies, the Spanish Agency of Medicines and Healthcare Products had previously issued its favourable resolution for the clinical trial by considering it meets all the healthcare and suitability requirements.

Furthermore, it stresses that it is "essential to transfer the scientific evidence generated by research on COVID-19 as soon as possible to clinical practice."

The idea came from our knowledge of the strong antiinflammatory and antithrombotic effect that the defibrotide medicine achieves when treating hepatic veno-occlusive disease, which is a very severe complication that patients who have undergone bone marrow transplant suffer, by protecting the endothelium.

Therein lies the key: the endothelium is composed of cells that line the inside of our veins and arteries. The endothelium opens or closes the passing of inflammatory cells from the blood to the tissues.

If we protect the endothelium, we will prevent the inflammatory cells from the innate and adaptative immune system from reaching the lung in response to the cytokine storm caused by the virus, which thus causes mass inflammation and the respiratory distress syndrome which is characteristic of COVID-19, as well as the microthrombosis that causes multiorgan failure and the death of these patients,"

Dr José María Moraleda, Head of the Haematology and Cell Therapy Service of the HCUVA and Professor of Haematology of Murcia University

First results in three months

The objective of the trial is to "show that defibrotide is efficient and safe as a therapy against COVID-19 and we believe it could decrease the mortality rate by 25% by ensuring that patients who were in intermediate phases of the disease do not worsen, thus preventing intubation.

Furthermore, those who are already intubated, improve, and mechanical respiratory assistance can be withdrawn," adds Doctor Moraleda.

For this purpose, 120 patients with different degrees of severity will be recruited (intubated and non-intubated) in the random clinical trial in a proportion of 2:1; in other words, there will be 80 patients who will receive experimental treatment with defibrotide and 40 more who will receive a placebo as a control group.

But all patients will be able to receive all the therapies that are currently being used to try to slow down the SARS-COV-2 infection, such as antivirals, hydroxychloroquine, steroids or tocilizumab, because defibrotide does not interact with any of them and is perfectly compatible.

It is worth noting that defibrotide is a very safe medicine, and it can currently be used with children and infants one month of age or older.

As well as the patients that will be recruited by the HCUVA, the trial will include infected people from other Spanish centres: the 'Jiménez Díaz' foundation and Hospital 12 de Octubre of Madrid, H. Clínic of Barcelona and H. U. of Salamanca, as well as H. U. Morales Meseguer.

Jazz Pharmaceuticals, the multinational pharmaceutical company responsible for defibrotide, has confirmed to the IMIB team that it will support this trial.

Doctor Moraleda specifies that "from day one, the company has shown to be very committed to the research of medicines that are already available such as defibrotide, to tackle the severe consequences of this disease, which has been decisive for this study to be conducted.

The main researcher of the trial stresses the fact that "we are obsessed with the scientific quality of the trial at a time of such therapeutic uncertainty." This project seeks to obtain scientific evidence, give hope to those affected based on the verified efficacy of the medicine, not the unverified opinion of experts with good will.

We hope to have the first results in around three months, with the data analysis that applying the therapy to the first patients offers us. We will start immediately, because "our patients desperately need efficient treatments with scientific guarantees." It also says that, in parallel, biological studies will be conducted to look further into the knowledge on the disease and the effects of the treatment.

Doctor Moraleda highlights the multidisciplinary nature of the trial and thanks the formidable effort and collaboration of the Haematology team and all the Departments that are directly involved in its development such as the Internal-Infectious Medicine, Intensive Care, Pharmacy, Clinical Analysis, Immunology, Radiology, Microbiology and Nursery Departments of the Hospital Clínico Universitario de la Arrixaca; as well as the efficient management of the FFIS and the aid of basic researchers of the IMIB and TerCel.

International collaboration

In parallel to the beginning of the clinical trial in Murcia, Doctor Moraleda stresses that a work group has already begun with prestigious researchers from international institutions in order to, in the near future, expand the clinical trial to other countries.

Specifically, international collaboration is being processed with professor Paul G. Richardson, who teaches at the Harvard Medical School and the Dana-Farber Cancer Institute (Boston, USA), professor Carmelo Carlo Stella, from the Cancer Center Humanitas Research Hospital (Milan, Italy), professor Favio Ciceri, from the San Rafaelle Institute (Milan, Italy), and professor Toni Pagliuca Kings Hospital (London, UK).

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