Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19) in Colombia

  • STATUS
    Recruiting
  • days left to enroll
    43
  • participants needed
    1200
  • sponsor
    Universidad Nacional de Colombia
Updated on 18 February 2021
diabetes
pneumonia
cancer
azithromycin
COPD
mechanical ventilation
lopinavir/ritonavir
respiratory distress
acute respiratory distress
FIO2
pao2
covid-19
SARS
organ failure
remdesivir
oximetry
PCR test
hydroxychloroquine
chloroquine
tocilizumab
coronavirus infection

Summary

Introduction: The COVID-19 pandemic is characterized by significant morbidity and mortality. It is caused by a novel coronavirus with no current specific prevention nor treatment therapies. Treatments have been administered to patients with COVID-19 in order to control viral infection, among them: Chloroquine (CQ) and Hydroxychloroquine (HCQ), Lopinavir/Ritonavir (Lop/r), Remdesivir, Favipavir, Emtricitabine/ Tenofovir acting over bacterial co-infection Azithromycin (Azithro), or modifying the inflammatory response of the host (Tocilizumab, colchicine, dexamethasone, Icatibant, ibuprofen lipidic and by other mechanisms (rosuvastatin) Clinical trials offer conflicting evidence regarding the effectiveness and safety of therapies The real effectiveness and safety profile of the treatments for COVID-19 remains unknown.

Objective: Evaluate the effectiveness and safety of pharmacological therapies used to treat adult patients with COVID-19.

Methods: Pragmatic randomized controlled trial. Study population: Adults aged 18 years or over with a positive real-time polymerase chain reaction (RT-PCR) or with high suspicion of Severe Acute Respiratory Syndrome CoV-2 (SARS CoV-2) and diagnosis of mild, severe or critical pneumonia, requiring hospital management at six hospitals in Colombia. Exclusion criteria: Pregnancy, known allergy to treatment, cirrhosis or hepatic abnormality (transaminases greater than 5 reference values), glomerular filtration rate lesser than 30 ml/min/1.73m^2, history of lung fibrosis, advanced or metastatic cancer. Sample size: 1,200 participants. The study will be carried out in two phases. The first phase will be conducted with 400 participants and aims to identify treatments with higher or minimum potential, discontinue treatments with higher toxicity and have opportunity of introducing new treatments with potential efficacy. The second phase will be conducted with 1,200 participants to evaluate the effectiveness of the selected treatments. Four interventions have been defined: I1 Emtricitabine/ teneofovir , I2 Colchicine plus rosuvastatin, I3 Emtricitabine/ teneofovir plus Colchicine plus rosuvastatin and I4 standard treatment. Within each institution, participants will be randomly assigned to one of the treatment arms assigned to that institution. Concealment will be kept through software that maintain the assignment concealed until the random assignment is done . Treatment administration will be open. Variables: Sociodemographic and clinical at recruitment; (comorbidities, need for therapeutic support , grade of invasion at admission). Primary outcomes. Effectiveness: Mortality. Safety: Serious adverse events (AE) assessed by the NCI Community Oncology Research Program (NCORP) Guidance for Collection of Adverse Events Related to COVID-19 Infection. Secondary outcomes: Intensive care unit (ICU) admission, requirement of respiratory support, time to death, number of participants cured, any adverse event related to treatment. Analysis: Descriptive for the presentation of summary measures of the basal conditions by type of variable. Bivariate. Description of the basal conditions (with organic failure at admission, without failure at admission), by type of treatment, by participating institution. Description of crude effectiveness and safety by means of the difference of accumulated incidences, each one with 95% confidence intervals (95% CI) Intention to treat analyisis will be done. Adjusted analysis: The ratio and difference of cumulative incidences of mortality at 7 and 28 days and severe adverse events between treatments will be estimated, adjusting for confounding variables using logistic regression models with mixed effects considering each institution as a level or from equations. generalized estimation (GEE). On the other hand, as part of the pragmatic approach, the surface under cumulative ranking curve (SUCRA) will be calculated based on Bayesian theory to define which drug has the highest probability of being the most useful in the management of infection.

Ethical considerations: The study has a risk beyond minimum according to the Resolution 8430/1993 of the Colombian Ministry of Health. Informed consent will be explained and signed if the patient is in condition to do so. This protocol will undergo evaluation by the ethics committee at each of the participating institutions and at the National University of Colombia. The protocol follows the Helsinki Declaration and institutional protocols for clinical investigation.

Description

Initially, the use of the drugs chloroquine, hydroxychloroquine and lopinavir / ritonavir had been proposed in this study, based on laboratory results of their in vitro antiviral potency for the CoV-2 virus, but with limited clinical evidence. However, later there were problems with the safety of the use of azithromycin in patients with SARS Covid 19. The coordinating committee of this study decided by consensus to suspend the use of hydroxychloroquine in the clinical trial in question by means of minutes of June 9, 2020 given that the interim analysis of the Recovery study showed (on June 5) that "there are no differences between hydroxychloroquine and standard treatment (28-day mortality between HCQ hydroxychloroquine and standard treatment (28-day mortality outcome (25.7% hydroxychloroquine vs. 23.5% usual care; Hazard ratio (HR: 1.11 [95% CI 0.98-1.26]). "(21) On the other hand, on June 29, the same Recovery study published the results of the interim analysis on the use of lopinavir ritonavir in patients with SARS Covid 19. In a statement it reports that "there were no significant differences in the 28-day mortality outcome (22.1% of lopinavir-ritonavir versus 21.3 % of usual care; (relative risk RR 1.04 95% CI 0.91-1.18]; no beneficial effects were found on the risk of progression to mechanical ventilation or the length of hospital stay "(22)

Given these results, it is relevant to know the clinical effectiveness and adverse effects of the drugs: emtricitabine / tenofovir, colchicine / rosuvastatin, compared with the usual management, as alternatives for the management of COVID-19 infection in real patient scenarios for support decision making in clinical practice.

Interim analysis and sample size

The study will be carried out in two stages, given the great uncertainty surrounding the safety and effectiveness of the treatments, as well as taking into account the speed in which evidence is appearing locally and globally. The first stage of the study will be carried out with a sample of 400 participants, with the aim of identifying the treatments with the greatest potential, as well as discarding early those treatments with the highest toxicity or lowest effectiveness, in order to introduce a new drug. In the second stage, with a sample of 1,200 participants, the effectiveness of the four treatments selected at the beginning of the second stage will be evaluated, which may be the same contained in the 3 active treatment arms and the standard management group or one or more new drugs arms. The total sample size of the study will be 1,200 participants.

Stage 1. Evaluation of the safety and minimum effectiveness of the selected treatments:

For this stage, a sample size of 400 participants collected from the 6 institutions was calculated, obtaining, for the four interventions, 100 participants for each intervention. Assuming a loss percentage of 10.

Safety evaluation: If a treatment presents in the first 30 participants 3 severe adverse events or if during the execution of this stage it reaches a percentage of severe adverse events greater than or equal to 10 percent, the drug will be withdrawn.

Evaluation of the minimum effectiveness:

When completing the sample size of this stage (400 participants), a interim analysis will be carried out that allows testing whether there is an expected difference of 15 percent (25 percent - 10 percent), with a power of 84 percent. As in the previous analysis, if significant differences are found, the treatment with less effectiveness (highest mortality) is replaced. The correction of the type I error will be made using the O'Brien-Fleming method.

Stage 2. Estimation of effectiveness:

With a sample size of 1,2ticipants were obtained for each intervention, allowing the evaluation of an expected difference of 10 (25 percent - 15 percent) with a power of 81 percent and a significance level of 0.05. A loss percentage of 10 will be considered.

Rules for selecting a drug to be included in the RCT in stage 2

Criteria for inclusion of a new drug, in its order:

  1. Evidence that the drug is safe in humans
  2. The drug must have a record from the National Institute for Food and Drug Surveillance (Invima)
  3. Drug's availability in the country
  4. The drug must show at least 15 percent superiority to standard management in other randomized clinical trials that have been conducted in patients with SARS CoV-2 / COVID-19
  5. Biological plausibility and studies that support the choice: in vitro case series studies, use in similar situations
  6. Ongoing studies that are evaluating the drug's effectiveness and safety
  7. The drug must meet the objective of the study

Details
Condition *COVID-19, Covid-19
Treatment Rosuvastatin, Standard Treatment, Emtricitabine/Tenofovir, Colchicine Pill
Clinical Study IdentifierNCT04359095
SponsorUniversidad Nacional de Colombia
Last Modified on18 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Covid-19 or *COVID-19?
Eligibility criteria for institutions
Centralized pharmacy department which allows safe storage of drugs
Centralized pharmacy department that follows good clinical practice protocols for investigation
and either
ICU capacity of at least 10 beds with available ventilatory support (volume) or
Intermediate care unit with at least 10 beds with partial ventilatory support
Inclusion criteria for participants
Age 18 years or over
Positive RT-PCR for COVID-19 or high suspicion of SARS covid 19
Requirement of in-hospital treatment, classified in any of the following categories
Mild pneumonia, defined as
Confirmed pneumonia with chest X-Rays
and at least 2 of the following risk factors or complications
Age 60 years or over
History of cardiovascular disease
History of diabetes mellitus (DM)
History of chronic obstructive pulmonary disease (COPD)
History of hypertension (HT)
Cancer
or
\. Moderate pneumonia, defined as
Confirmed pneumonia with chest X-Rays
and either
Criteria for in-hospital management according to the simplified confusionrespiratory rate- blood pressure- age scale (CRB-65 scale) score greater than 1 or Oxygen saturation lower than 90 percent without supplementary oxygen
or
\. Severe pneumonia, sepsis or septic shock, defined as
Confirmed pneumonia with chest X-Rays and either
Criteria for in-hospital management according to the simplified CRB-65 scale (score greater than 1) or
Oxygen saturation lower than 90 percent without supplementary oxygen
and any of the following
Respiratory rate greater than 30 per minute
Need for mechanical ventilation (invasive or non-invasive)
Sepsis defined as organic dysfunction which can be identified by a Sequential Organ Failure Assessment score (SOFA score) of at least 2 points
Quick sequential organ failure assessment score (qSOFA) score with 2 of the following
criteria
Glasgow of 13 or lower, systolic blood pressure of 100 mmHg or lower and respiratory rate equal to or higher than 22 per minute
Arterial hypotension which persists after hydric resuscitation and requires vasopressors to maintain a mean arterial pressure greater than 65 mmHg and lactate lesser than 2 mmol/L (18 mg/dL) without hypovolemia (referred as septic shock)
Multiple organ failure
Acute Respiratory Distress Syndrome (radiological findings compatible with bilateral infiltrates and oxygenation deficit classified as: mild (PaO2/FiO2 between 200 and 300), moderate (PaO2/FiO2 between 100 and 200) or severe (PaO2/FiO2 lower than 100))

Exclusion Criteria

Pregnancy
Known allergies to the drugs under study
Hepatic cirrhosis (Child B or C) or hepatic abnormality manifested as transaminase levels 5 times above reference values
Glomerular filtration rate lesser than 30 ml/min/1.73^m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
Advanced or metastatic cancer
Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight questionnaire (FRAIL) score of fragility greater than 3
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