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

Introduction: The COVID-19 pandemic is characterized by significant morbidity and mortality. Treatments have been administered to patients with COVID-19 in order to control viral infection, among them: 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, and by other mechanisms (rosuvastatin). Except for dexamethasone clinical trials offer conflicting evidence regarding the effectiveness and safety of therapies.

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. A sample size was calculated from a sensitivity analysis with three scenarios:

scenario 1 a total of 1,163 patients, that is, 291 per treatment arm with alpha of Alpha = 0.05; power 0.8; Prop1 = 0.2 and Prop2 = 0.1 (expected difference of 10%) and 10% of possible losses,scenario 2. With the previous parameters and with a Prop1 = 0.15 and Prop2 = 0.05 for a total of 814 patients (204 per arm of treatment). scenario 3. With Alpha = 0.1, Prop1 = 0.15 and Prop2 = 0.05, the other previous parameters, for a total of 686 patients (172 per treatment). in scenario 1 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 the opportunity of introducing new treatments with potential efficacy. The second phase will be conducted with 1,163 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.

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

A sample size was calculated from a sensitivity analysis with three scenarios:

scenario 1 a total of 1,163 patients, that is, 291 per treatment arm with alpha of Alpha = 0.05; power 0.8; Prop1 = 0.2 and Prop2 = 0.1 (expected difference of 10%) and 10% of possible losses, scenario 2. With the previous parameters and with a Prop1 = 0.15 and Prop2 = 0.05 for a total of 814 patients (204 per arm of treatment) scenario 3. With Alpha = 0.1, Prop1 = 0.15 and Prop2 = 0.05, the other previous parameters, for a total of 686 patients (172 per treatment).

A sample size was calculated from a sensitivity analysis with three scenarios:

scenario 1 a total of 1,163 patients, that is, 291 per treatment arm with alpha of Alpha = 0.05; power 0.8; Prop1 = 0.2 and Prop2 = 0.1 (expected difference of 10%) and 10% of possible losses, scenario 2. With the previous parameters and with a Prop1 = 0.15 and Prop2 = 0.05 for a total of 814 patients (204 per arm of treatment) scenario 3. With Alpha = 0.1, Prop1 = 0.15 and Prop2 = 0.05, the other previous parameters, for a total of 686 patients (172 per treatment)

Under this new approach we will make an evaluation of the minimum effectiveness in scenarios 1 and 2 :

Stage 1 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:

When we have a sample size of 290 participants in each intervention, allowing the evaluation of an expected difference of 10 (20percent - 10 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 1

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

In the scenario 2 and 3 we will no do an interim analysis

Eligibility Criteria:
Inclusion Criteria:

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:

1. 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
2. Moderate pneumonia, defined as :

   - Confirmed pneumonia with chest X-Rays

   and either

   - Criteria for in-hospital management according to the simplified confusion- respiratory rate- blood pressure- age scale (CRB-65 scale) score greater than 1 or Oxygen saturation lower than 90 percent without supplementary oxygen.

   or
3. 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 for participants:

* 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