Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19) in Colombia
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| ClinicalTrials.gov Identifier: NCT04359095 |
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Recruitment Status :
Completed
First Posted : April 24, 2020
Last Update Posted : August 12, 2021
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| COVID-19 | Drug: Emtricitabine/tenofovir Drug: Colchicine Pill Drug: Rosuvastatin Other: Standard treatment | Phase 2 Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 650 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19) in Colombia: A Pragmatic Randomized Controlled Trial |
| Actual Study Start Date : | August 18, 2020 |
| Actual Primary Completion Date : | March 20, 2021 |
| Actual Study Completion Date : | June 30, 2021 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: I1 Emtricitabine + Tenofovir
Intervention 1: Emtricitabine (200 mg) + tenofovir (300 mg): 500 mg once a day for 10 days
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Drug: Emtricitabine/tenofovir
Generic drug distributed by the Colombian Health System for Human Immunodeficiency Virus (HIV) positive patients It is classified as an anti infectious drug and its current indications include HIV infections.
Other Name: Truvada ® |
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Active Comparator: I2 Colchicine + rosuvatatine
Intervention 2: Colchicine: 0.5 mg every 12 hours for 14 days + Rosuvatatin: 40 mg / day for 14 days
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Drug: Emtricitabine/tenofovir
Generic drug distributed by the Colombian Health System for Human Immunodeficiency Virus (HIV) positive patients It is classified as an anti infectious drug and its current indications include HIV infections.
Other Name: Truvada ® Drug: Colchicine Pill Generic drug distributed by the Colombian Health System as an insurance treatment for Gout. It has been suggested that colchicine would be useful in SARS Covid 19 becouse its antiinflammatory effects through reduction of cytokine levels as well as the activation of macrophages, neutrophils, and the inflammasome |
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Active Comparator: I3 Emtricitabine/ tenofobir + colchicine+ rosuvastatin
Intervention 3: Emtricitabine (200 mg) + tenofovir (300 mg): 500 mg once a day for 10 days + Colchicine: 0.5 mg every 12 hours for 14 days + Rosuvatatin: 40 mg / day for 14 days
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Drug: Emtricitabine/tenofovir
Generic drug distributed by the Colombian Health System for Human Immunodeficiency Virus (HIV) positive patients It is classified as an anti infectious drug and its current indications include HIV infections.
Other Name: Truvada ® Drug: Rosuvastatin Generic drug distribute by the Colombian Health System. It is used in people with High levels of cholesterol. An action against the main protease (Mpro) of COVID 19 virus has been described, There is evidence suggesting that statins could exert anti Covid 19 action and the infectivity of enveloped viruses
Other Name: Crestor ® Rosuvas ® |
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I4 Standard Treatment
Intervention 4: Standard treatment. It is defined as treatment aimed to control symptoms including fever and pain, multiple organ failure related to the acute infection including respiratory support (oxygen, positive end-expiration pressure with external devices or invasive ventilatory support), cardiovascular, renal, haematological or coagulation, or co-infection with bacterial or mycotic organisms, standard care to prevent pressure ulcers or other care required by the patient, might include Dexamethasone. No viral therapies are included.
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Other: Standard treatment
Standard treatment n, multiple organ failure related to the acute infection including respiratory support (oxygen, positive end-expiration pressure with external devices or invasive ventilatory support), cardiovascular, renal, haematological or coagulation, or co-infection with bacterial or mycotic organisms, standard care to prevent pressure ulcers or other care required by the patient. No viral therapies are included. |
- Mortality [ Time Frame: Post-intervention at day 28 ]Cumulative incidence
- Number of Participants with Treatment Related Severe Adverse Events as Assessed by the NCORP Guidance for Collection of Adverse Events Related to COVID-19 Infection [ Time Frame: Post-intervention at day 28 ]Number of participants that develop severe adverse events related to the treatment
- Mortality [ Time Frame: Post-intervention at day 7 ]Cumulative incidence
- Number of Participants with Treatment Related Severe Adverse Events as Assessed by the NCORP Guidance for Collection of Adverse Events Related to COVID-19 Infection [ Time Frame: Post-intervention at day 7 ]Number of participants that develop severe adverse events related to the treatment
- Time to death [ Time Frame: Assessed up to 28 days postintervention ]Time from the date of assignment until the date of death from any cause
- Number of Participants that are transferred to the Intensive Care Unit (ICU) [ Time Frame: Post-intervention at day 28 ]Number of Participants that require management in the ICU
- Number of Participants that need Mechanical Ventilation Support with endotracheal intubation. [ Time Frame: Up to 28 days after hospital admission ]Participants requiring invasive mechanical ventilation
- Number of participants Cured assessed by Nasopharyngeal swab, oropharyngeal swab, and blood aspiration for COVID19 (RT-PCR) without clinical symptoms and normal chest X ray [ Time Frame: Up to 28 days after hospital admission ]Number of participants cured assessed RT-PCR for SARS CoV-2, without clinical symptoms and no radiological signs assessed by chest X ray
- Number of Participants with Any Adverse Event Related to Treatment Assessed by the NCORP Guidance for Collection of Adverse Events Related to COVID-19 Infection [ Time Frame: Up to 28 days after hospital admission ]Any adverse event
- Severe Adverse events [ Time Frame: Up to 28 days after hospital admission ]Interim assessment of safety, which will be conducted after 400 number of participants with severe adverse events divided by the total number of participants treated). It aims to aid the decision of excluding an active treatment arm should that arm have more than 3 serious adverse events in the first 30 participants or a serious adverse events incidence of 10 percent or higher.
- Mortality [ Time Frame: Up to 28 days after hospital admission ]Interim assessment of minimum effectiveness, which will be conducted after 480 participants are recruited. It will be evaluated through relative frequency measurements (mortality proportion at 28 days of treatment). It aims to aid the decision of excluding an active treatment arm should that treatment arm have an efficacy lower than 0.2, calculated through futility analysis that assumes an expected difference of 10 percent at the end of the first phase of the study. For all the tests carried out in the interim analysis, the correction of the type I error will be made using the O'Brien-Fleming method.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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:
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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
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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
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04359095
| Colombia | |
| Clinica santa Maria del lago | |
| Bogota, DC, Colombia, 110111 | |
| Clínica Reina Sofía | |
| Bogotá, Colombia, 110121 | |
| Fundacion Cardio Infantil | |
| Bogotá, Colombia, 110131 | |
| Hospital Universitario San Ignacio | |
| Bogotá, Colombia, 110231 | |
| Clinica Universitaria Colombia | |
| Bogotá, Colombia, 111321 | |
| Hospital Universitario Nacional de Colombia | |
| Bogotá, Colombia, 111321 | |
| Principal Investigator: | Hernando Gaitán, MD | Universidad Nacional de Colombia |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Hernando Gaitán, MD, Professor at the Obstetrics and Gynecology Department and Clinical Research Institute. Director of Research and Extension in the Bogota Campus at The Universidad Nacional de Colombia, Co- Ed. Sexually Transmitted Infections Cochrane Review Group, Universidad Nacional de Colombia |
| ClinicalTrials.gov Identifier: | NCT04359095 |
| Other Study ID Numbers: |
76968 |
| First Posted: | April 24, 2020 Key Record Dates |
| Last Update Posted: | August 12, 2021 |
| Last Verified: | August 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Communicating trial results and data to be able to combine data from multiple studies (live SR) |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (CSR) Analytic Code |
| Time Frame: | As soon we have checked the quality of data of recruited participants |
| Access Criteria: | Approved by the monitor committee of the study |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | Yes |
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COVID-19 COVID-19 drug treatment |
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COVID-19 Pneumonia, Viral Pneumonia Respiratory Tract Infections Infections Virus Diseases Coronavirus Infections Coronaviridae Infections Nidovirales Infections RNA Virus Infections Lung Diseases Respiratory Tract Diseases Tenofovir Emtricitabine Colchicine |
Rosuvastatin Calcium Antiviral Agents Anti-Infective Agents Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Anticholesteremic Agents Hypolipidemic Agents Antimetabolites Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Gout Suppressants |