Benefits were observed in a clinical trial involving 38 volunteers treated at the teaching hospital of the University of São Paulo’s Ribeirão Preto Medical School. The drug is cheap and can shorten ICU stays but should not be used outside hospitals, the researchers warn (photo: FMRP-USP)
Published on 03/19/2021
By Karina Toledo | Agência FAPESP – The results of a clinical study conducted by researchers at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil show that colchicine, a drug that for decades has been used to treat gout, can help combat lung inflammation so that patients recover faster from moderate to severe COVID-19.
The study was supported by FAPESP. A preprint (not yet peer-reviewed) paper reporting the findings is published on medRxiv.
“Volunteers treated with colchicine stopped needing supplemental oxygen three days sooner on average than patients treated according to the hospital’s standard protocol. They were also able to go home sooner,” Renê Oliveira, principal investigator for the study, told Agência FAPESP. Oliveira is an attending physician in the teaching hospital run by FMRP-USP.
According to Paulo Louzada Junior, a professor at FMRP-USP and a co-author of the paper, the reduction in the time required for patients to recover could represent a significant saving for public healthcare services and enable them to treat more people per period. “Treatment in intensive care units [ICUs] can cost between 5,000 and 10,000 Brazilian Reais per patient per day,” he said. “Oxygen supplementation is also expensive, even outside the ICU. Colchicine is a cheap drug and has the potential to be used on a large scale. In our case the complete treatment cost about 30 BRL per patient.”
Another advantage of the drug, according to the researchers, is that its adverse side-effects (mainly diarrhea) are well-known to physicians. “Overall, colchicine is considered safe, but it should be stressed that in the case of COVID-19 the benefits were observed in hospitalized patients with some degree of lung impairment. We don’t recommend indiscriminate use of the drug either for prevention or for treatment of mild symptoms of the disease,” Louzada Junior said.
Even for hospitalized patients, the benefits still need to be confirmed in a trial with a larger number of participants. “We’ve applied to CONEP [the Health Ministry’s Research Ethics Commission] for permission to proceed to the next stage and we’ll start recruiting volunteers soon,” Oliveira said.
Gold standard
To test the hypothesis that colchicine can attenuate the inflammatory cytokine storm seen in severe cases of COVID-19, the researchers conducted a controlled randomized double-blind clinical trial between April 1 and July 6. This type of trial is considered the gold standard guide to clinical practice, since neither the physicians nor the patients know who actually takes the compound being tested and this reduces the risk of biases such as selecting more severe patients for treatment.
The 38 participants were randomly divided into two groups. Both were treated according to the hospital’s standard protocol for COVID-19. One group was also given colchicine, while the other was given placebo. The trial was conducted under the aegis of the Center for Research on Inflammatory Diseases (CRID), hosted by FMRP-USP. CRID is one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.
Patients were included in the study if they displayed respiratory failure and had to be hospitalized to receive supplemental oxygen. “We didn’t include intubated intensive care patients, but colchicine could safely be used in these cases as well. This patient profile may be included in the next phase of the clinical trial,” Oliveira said.
The results described in the paper refer to 35 of the 38 participants, 18 in the control group given placebo and 17 in the group treated with colchicine. One volunteer had to be transferred to the ICU before the start of protocol medication. Two others (one in the group that received colchicine and one in the control group) had to be transferred to the ICU during treatment and hence did not complete the observation period. None of the 38 volunteers died.
When they compared the outcomes for the two groups, the researchers concluded that colchicine benefited patients in three ways: it reduced the length of time during which they required oxygen therapy, it shortened hospital stay, and it reduced C-reactive protein levels faster. C-reactive protein is considered the main marker of systemic inflammation.
“After seven days of treatment with the drug, levels of inflammatory markers returned to normal,” Louzada Junior said.
Oliveira explained that colchicine acts mainly on two types of immune system cell, neutrophils and macrophages, reducing production of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and lowering levels of interleukin-6 (IL-6) and tumor necrosis factor as a result. The first two cytokines are the main drivers of joint inflammation in patients with gout.
“The first studies involving severe COVID-19 patients showed significantly augmented blood levels of these cytokines, especially IL-1β. So we thought colchicine might have a beneficial effect by reducing the lung inflammation that leads to respiratory failure,” he said.
The next phase of the clinical trial will be open, meaning no information will be withheld. Patients will be invited to participate and will know if they are given the medication. The inclusion criteria will be less restrictive. Patients with cancer and other chronic diseases will be able to take part, for example, Oliveira said.
The article “Beneficial effects of colchicine for moderate to severe COVID-19: an interim analysis of a randomized, double-blinded, placebo controlled clinical trial” can be retrieved from: www.medrxiv.org/content/10.1101/2020.08.06.20169573v2.full.pdf.
Source: https://agencia.fapesp.br/33958
