A recent clinical study conducted in Barcelona supports the use of two combination drugs (colchicine and prednisone) in elderly patients with COVID-19 who need oxygen. The study provides results that support the efficacy of this drug in this class of patients. The FRAGILE-COLCOVID19 clinical study published a few days ago in the international journal Clinical investigation of drugs It was carried out on elderly people admitted to two geriatric centers, the Geriatrics Unit of the Internal Medicine Service of the Hospital Clínic de Barcelona and in the health and social center of the Sant Antoni Clinic. The drugs studied are colchicine and prednisone, two drugs with anti-inflammatory and immunomodulatory properties, widely used for their effectiveness in inflammatory and autoimmune diseases.
The FRAGILE-COLCOVID clinical trial19 was designed as a randomized trial that investigated the efficacy and safety in COVID-19 of early oral administration of two anti-inflammatory drugs compared to intravenous dexamethasone, the only drug authorized to date. All patients were over 65 with SARS-CoV-2 virus pneumonia and oxygen requirements. This research was led by Dr. José Hernández-Rodríguez, internist at the Autoimmune Diseases Service of the Hospital Clínic de Barcelona, and benefited from the co-investigation of Dr. Alfonso López-Soto, Head of the Internal Medicine of the same hospital, and Dr. Julio Durán Sanclemente, coordinator geriatrician of the Sant Antoni Clinic, a socio-health center near the Hospital Clínic.
initial idea
The initial idea for this study was born, at the height of the devastating first wave of COVID-19, from the collaboration between Dr. Hernández-Rodríguez and Dr. José Luis Blanco, internist at the Hospital Clínic Infectious Diseases Service. Dr Hernández explains that “although during the first months of 2020 there was no clear evidence of how this new infection was produced and how it could be treated, like other researchers around the world, we considered from the beginning that the final cause of death of patients with SARS-CoV-2 pneumonia was mainly a very powerful and generalized inflammatory response caused by the virus, but especially in the lungs “.
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For this reason, continues Dr. Blanco, “the intention of the FRAGILE-COLCOVID19 study was to be able to offer treatment to patients who were going through the worst period, which were undoubtedly elderly patients hospitalized in residences and other geriatric centers, considered from the beginning fragile and vulnerable for their age, but in that period even more so, because structural resources, health personnel, medicines and the ability to move to hospital were very scarce or absent in the centers where they were located .
In this way, a combination of two drugs was considered that could be administered orally and without excessive complications, and those chosen were colchicine, a powerful anti-inflammatory used in gout and other inflammatory diseases, and prednisone, the corticosteroid. more common. used orally in our country, and with known utility in inflammatory and autoimmune processes “.
Dr. López-Soto and Dr. Durán Sanclemente played a key role in facilitating the study in the two geriatric centers. The research group is also composed of doctors Sergio Prieto and Olga Araújo, Ms. Teresa Hospital, the nurse in charge of the study, and all members of the FRAGILE-COLCOVID19 Study Group.
The researchers acknowledge that “at that early stage we already knew that the hypothesis that led to the design of the study was bold, but so were most of the measures taken against the grain in the first weeks and months of the pandemic. This boldness included many. of the drugs that came into use in the bewildering early period and never proved useful. Dr. Hernández clarifies that “in the case of corticosteroids, these were initially advised against in many hospital centers for patients admitted for COVID-19, as they have been attributed harmful properties against viral infection “.
In fact, they did not begin to be administered routinely until June 2020, when the British clinical study led by Dr. Martin Landray was published, which showed that dexamethasone (a corticosteroid) reduced the mortality of patients with COVID. 19 needed oxygen. Since other types of corticosteroids have also been shown to be effective in COVID-19, all experts agree that the use of corticosteroids was a turning point in the pandemic, as their routine application clearly increased the survival of hospitalized patients. in hospital for COVID-19.
In parallel, some researchers have thought that colchicine, given its intense and rapid anti-inflammatory effects in diseases with a clear inflammatory component such as gout, through mechanisms other than those of prednisone, could also be useful in curbing the exaggerated inflammation that occurs. in cases of severe COVID-19. Regarding this drug, Dr. Hernández notes that “knowledge of the results of the international study conducted by Canadian physician Jean Claude Tardif has also given us high hopes, in which colchicine has already offered some benefits in patients with mild COVID-19 who are not have to enter. “
Design and results
The FRAGILE-COLCOVID study19 consisted of half of the patients receiving the experimental treatment (colchicine and prednisone) and the other half receiving the already approved treatment (intravenous dexamethasone). In patients treated with the study combination, the total duration of treatment was 14 days. The first three days they received a daily dose of prednisone and two or three doses of colchicine, and from the fourth day, a single dose of colchicine until the completion of 14 days. Patients who died or worsened were screened and had to be given other intravenous treatments or were referred to the Intensive Care Unit (ICU). Several variables were also studied that marked the clinical and biological evolution in both groups of patients. In addition, the safety of colchicine and prednisone was investigated by evaluating side effects in all patients for 28 days.
Of the 144 patients initially planned to be included in the study, only 54 patients could be recruited. During the 28 days of the study, worsening due to initial therapy failure or death occurred in 45% of patients who received intravenous dexamethasone and in 28% of those who were treated with the combination of colchicine and prednisone . The statisticians involved in the analysis of the results were Dr. Víctor Sapena and Dr. Georgina Casanovas.
Dr Hernández clarifies that “the statistical analysis of these results showed an overall risk reduction of 17% and a relative risk reduction of worsening or death of 39% in favor of patients who received colchicine and prednisone. Despite these results. positive, what is known in science has not reached “statistical significance”, for this reason these results must be interpreted only as a trend in favor of experimental drugs “.
However, continues Dr. Hernández, “Other variables analyzed, such as the overall need for corticosteroids and the reduction in analytical parameters of inflammation, were found to be significantly favorable to the combination of the two drugs. It is also important to emphasize that no observed differences in adverse effects were found in patients of the two. groups, and therefore it can be ensured that the safety margin of prednisone and colchicine is perfectly acceptable “.
The publication comments that the study has some limitations. In this sense, Dr. Hernández clarifies that “the limitations of a study are all the circumstances that cause the information to be no more precise and, in our case, not including all the patients initially planned could reduce the power of the statistical study “. When asked, what factors intervened in the fact that the final sample was smaller than expected ?, the doctor replies that “a certain initial reluctance to carry out the study, together with the difficulty of its financing, delayed its start.
The use of other drugs, such as those included in other clinical trials, also reduced the potential for patient entry. Finally, the only limiting factor that we were extremely satisfied with was the arrival of the long-awaited vaccines, which allowed the patients not to get worse, and therefore caused the clinical trial to close prematurely. “
Conclusions
The conclusion that can be drawn from the FRAGILE-COLCOVID19 study and the results generated from previous clinical studies is that in geriatric patients with moderate COVID-19 (those who have an initial need for oxygen therapy), early oral administration of colchicine and prednisone has shown effects survival benefits for these patients. This drug combination is normally well tolerated and has no notable side effects. From now on, it could have practical use in COVID-19 patients who are in vulnerable situations, such as those from countries with fewer resources without access to vaccines or who are not well immunized.
The researchers of the clinical trial are grateful for the support received by the Fundació Clínic per la Recerca Biomèdica (FCRB), promoter of the study, and by the Hospital Pharmacy Service and highlight the economic contribution of the SEID Laboratories and the Sponsorship Area of l’Hospital Clínic de Barcelona crucial to be able to conclude the study. They also appreciate the attitude “of all the patients who participated in the study and their families, who in a very difficult and critical personal and circumstantial situation contributed with their generosity and confidence to increase knowledge about possible treatments for COVID- 19 “.
