COVID-19Phase 2/3NCT04359095
Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19) in Colombia
A Phase 2/3 study testing Emtricitabine/tenofovir, Colchicine Pill and Rosuvastatin in people with COVID-19, run by Universidad Nacional de Colombia at 6 sites in Colombia.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- COVID-19
- What is being tested?
- Emtricitabine/tenofovir, Colchicine Pill and Rosuvastatin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 650 participants
- Where
- 6 sitesColombia
- Study dates
- 18 Aug 2020to 30 Jun 2021
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 37Show fewer
- 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 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
- 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)).
Who cannot join
- 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
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Colombia6 sites
Clinica santa Maria del lago
Bogotá, DC, 110111
Clínica Reina Sofía
Bogotá, 110121
Fundacion Cardio Infantil
Bogotá, 110131
Hospital Universitario San Ignacio
Bogotá, 110231
Clinica Universitaria Colombia
Bogotá, 111321
Hospital Universitario Nacional de Colombia
Bogotá, 111321
About this study
Official title: Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19) in Colombia: A Pragmatic Randomized Controlled Trial
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.
Read more
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.
Read the detailed 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
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:
- Evidence that the drug is safe in humans
- The drug must have a record from the National Institute for Food and Drug Surveillance (Invima)
- Drug's availability in the country
- 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
- Biological plausibility and studies that support the choice: in vitro case series studies, use in similar situations
- Ongoing studies that are evaluating the drug's effectiveness and safety
- The drug must meet the objective of the study
In the scenario 2 and 3 we will no do an interim analysis
- Conditions
- COVID-19
- Being tested
- Emtricitabine/tenofovir, Colchicine Pill, Rosuvastatin, Standard treatment
- Keywords
- COVID-19, COVID-19 drug treatment
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Emtricitabine/tenofovirDrug
Also called Truvada ®
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.
Colchicine PillDrug
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
RosuvastatinDrug
Also called Crestor ® Rosuvas ®
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
Standard treatmentOther
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.
| Study group | Role | What they receive |
|---|---|---|
| I1 Emtricitabine + Tenofovir | Active comparator | Intervention 1: Emtricitabine (200 mg) + tenofovir (300 mg): 500 mg once a day for 10 days Receives: Drug: Emtricitabine/tenofovir |
| I2 Colchicine + rosuvatatine | Active comparator | Intervention 2: Colchicine: 0.5 mg every 12 hours for 14 days + Rosuvatatin: 40 mg / day for 14 days Receives: Drug: Emtricitabine/tenofovir; Drug: Colchicine Pill |
| I3 Emtricitabine/ tenofobir + colchicine+ rosuvastatin | Active comparator | 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 Receives: Drug: Emtricitabine/tenofovir; Drug: Rosuvastatin |
| I4 Standard Treatment | Other | 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. Receives: Other: Standard treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Cumulative incidence
Measured: Post-intervention at day 28
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
Number of participants that develop severe adverse events related to the treatment
Measured: Post-intervention at day 28
Secondary outcomes (7)
Mortality
Cumulative incidence
Measured: Post-intervention at day 7
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
Number of participants that develop severe adverse events related to the treatment
Measured: Post-intervention at day 7
Time to death
Time from the date of assignment until the date of death from any cause
Measured: Assessed up to 28 days postintervention
Number of Participants that are transferred to the Intensive Care Unit (ICU)
Number of Participants that require management in the ICU
Measured: Post-intervention at day 28
Number of Participants that need Mechanical Ventilation Support with endotracheal intubation.
Participants requiring invasive mechanical ventilation
Measured: Up to 28 days after hospital admission
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
Number of participants cured assessed RT-PCR for SARS CoV-2, without clinical symptoms and no radiological signs assessed by chest X ray
Measured: Up to 28 days after hospital admission
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
Any adverse event
Measured: Up to 28 days after hospital admission
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2020
- Study start18 Aug 2020
- Primary completion20 Mar 2021
- Study completion30 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 650 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universidad Nacional de Colombia
- Sponsor type
- University, hospital or other
- Collaborators
- Pontificia Universidad Javeriana, Clínica Colsanitas-Clínica Universitaria Colombia, Hospital Universitario San Ignacio, Hospital Universitario Nacional de Colombia (HUN), Fundación Cardioinfantil Instituto de Cardiología, Clínica Infantil Santa María del Lago
- Responsible party
- Principal investigator, Hernando Gaitán, MD, Universidad Nacional de Colombia
- Investigators
- Hernando Gaitán, MD, Principal investigator, Universidad Nacional de Colombia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04359095
- Sponsor's protocol ID
- 76968
- Status last verified
- Aug 2021
- First submitted
- 15 Apr 2020
- Last updated
- 12 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Communicating trial results and data to be able to combine data from multiple studies (live SR)
Publications
Hatem A, Mohamed S, Abu Elhassan UE, Ismael EAM, Rizk MS, El-Kholy A, El-Harras M. Clinical characteristics and outcomes of patients with severe acute respiratory infections (SARI): results from the Egyptian surveillance study 2010-2014. Multidiscip Respir Med. 2019 Apr 1;14:11. doi: 10.1186/s40248-019-0174-7. eCollection 2019.
PubMed 30976418Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
PubMed 32109013Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. N Engl J Med. 2020 Feb 20;382(8):692-694. doi: 10.1056/NEJMp2000929. Epub 2020 Jan 24. No abstract available.
PubMed 31978293Zu ZY, Jiang MD, Xu PP, Chen W, Ni QQ, Lu GM, Zhang LJ. Coronavirus Disease 2019 (COVID-19): A Perspective from China. Radiology. 2020 Aug;296(2):E15-E25. doi: 10.1148/radiol.2020200490. Epub 2020 Feb 21.
PubMed 32083985Asociación Colombiana de Infectología. Consenso Colombiano de atención, diagnóstico y manejo de la Infección por SARS COV-2 / COVID 19 en establecimientos de atención de la salud. 2020.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4. No abstract available.
PubMed 32020029Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Jul 28;71(15):732-739. doi: 10.1093/cid/ciaa237.
PubMed 32150618Mo Y, Fisher D. A review of treatment modalities for Middle East Respiratory Syndrome. J Antimicrob Chemother. 2016 Dec;71(12):3340-3350. doi: 10.1093/jac/dkw338. Epub 2016 Sep 1.
PubMed 27585965Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.
PubMed 32187464Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 May;55(5):105938. doi: 10.1016/j.ijantimicag.2020.105938. Epub 2020 Mar 12.
PubMed 32171740Romanelli F, Smith KM, Hoven AD. Chloroquine and hydroxychloroquine as inhibitors of human immunodeficiency virus (HIV-1) activity. Curr Pharm Des. 2004;10(21):2643-8. doi: 10.2174/1381612043383791.
PubMed 15320751Yan Y, Zou Z, Sun Y, Li X, Xu KF, Wei Y, Jin N, Jiang C. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013 Feb;23(2):300-2. doi: 10.1038/cr.2012.165. Epub 2012 Dec 4. No abstract available.
PubMed 23208422Khan M, Santhosh SR, Tiwari M, Lakshmana Rao PV, Parida M. Assessment of in vitro prophylactic and therapeutic efficacy of chloroquine against Chikungunya virus in vero cells. J Med Virol. 2010 May;82(5):817-24. doi: 10.1002/jmv.21663.
PubMed 20336760Farias KJ, Machado PR, de Almeida Junior RF, de Aquino AA, da Fonseca BA. Chloroquine interferes with dengue-2 virus replication in U937 cells. Microbiol Immunol. 2014 Jun;58(6):318-26. doi: 10.1111/1348-0421.12154.
PubMed 24773578Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19.
PubMed 32074550
Study at a glance
From the registry record, last updated by the sponsor on 12 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19) in Colombia: A Pragmatic Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT04359095
- Acronym / sponsor ID
- 76968
- Conditions
- COVID-19
- Keywords
- COVID-19, COVID-19 drug treatment
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 650 participants (actual)
- Lead sponsor
- Universidad Nacional de ColombiaUniversity, hospital or other
- Collaborators
- Pontificia Universidad Javeriana, Clínica Colsanitas-Clínica Universitaria Colombia, Hospital Universitario San Ignacio, Hospital Universitario Nacional de Colombia (HUN), Fundación Cardioinfantil Instituto de Cardiología, Clínica Infantil Santa María del Lago
- Study start
- 18 Aug 2020 (actual)
- Primary completion
- 20 Mar 2021 (actual)
- Study completion
- 30 Jun 2021 (actual)
- First posted
- 24 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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
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:
- Evidence that the drug is safe in humans
- The drug must have a record from the National Institute for Food and Drug Surveillance (Invima)
- Drug's availability in the country
- 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
- Biological plausibility and studies that support the choice: in vitro case series studies, use in similar situations
- Ongoing studies that are evaluating the drug's effectiveness and safety
- The drug must meet the objective of the study
In the scenario 2 and 3 we will no do an interim analysis
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| I1 Emtricitabine + Tenofovir | Active comparator | Drug: Emtricitabine/tenofovirIntervention 1: Emtricitabine (200 mg) + tenofovir (300 mg): 500 mg once a day for 10 days |
| I2 Colchicine + rosuvatatine | Active comparator | Drug: Emtricitabine/tenofovir, Drug: Colchicine PillIntervention 2: Colchicine: 0.5 mg every 12 hours for 14 days + Rosuvatatin: 40 mg / day for 14 days |
| I3 Emtricitabine/ tenofobir + colchicine+ rosuvastatin | Active comparator | Drug: Emtricitabine/tenofovir, Drug: RosuvastatinIntervention 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 |
| I4 Standard Treatment | Other | Other: Standard treatmentIntervention 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (37 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Emtricitabine/tenofovirAlso: Truvada ®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. | Drug | I1 Emtricitabine + Tenofovir, I2 Colchicine + rosuvatatine, I3 Emtricitabine/ tenofobir + colchicine+ rosuvastatin |
| Colchicine PillGeneric 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 | Drug | I2 Colchicine + rosuvatatine |
| RosuvastatinAlso: Crestor ® Rosuvas ®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 | Drug | I3 Emtricitabine/ tenofobir + colchicine+ rosuvastatin |
| Standard treatmentStandard 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. | Other | I4 Standard Treatment |
Primary outcome
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
7 secondary outcomes
Mortality
Time frame: Post-intervention at day 7
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
Time to death
Time frame: Assessed up to 28 days postintervention
Number of Participants that are transferred to the Intensive Care Unit (ICU)
Time frame: Post-intervention at day 28
Number of Participants that need Mechanical Ventilation Support with endotracheal intubation.
Time frame: Up to 28 days after hospital admission
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 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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Aug 2021.
- Results publication: PubMed 30976418Hatem A, Mohamed S, Abu Elhassan UE, Ismael EAM, Rizk MS, El-Kholy A, El-Harras M. Clinical characteristics and outcomes of patients with severe acute respiratory infections (SARI): results from the Egyptian surveillance study 2010-2014. Multidiscip Respir Med. 2019 Apr 1;14:11. doi: 10.1186/s40248-019-0174-7. eCollection 2019.
- Results publication: PubMed 32109013Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
- Results publication: PubMed 31978293Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. N Engl J Med. 2020 Feb 20;382(8):692-694. doi: 10.1056/NEJMp2000929. Epub 2020 Jan 24. No abstract available.
- Results publication: PubMed 32083985Zu ZY, Jiang MD, Xu PP, Chen W, Ni QQ, Lu GM, Zhang LJ. Coronavirus Disease 2019 (COVID-19): A Perspective from China. Radiology. 2020 Aug;296(2):E15-E25. doi: 10.1148/radiol.2020200490. Epub 2020 Feb 21.
- Results publicationAsociación Colombiana de Infectología. Consenso Colombiano de atención, diagnóstico y manejo de la Infección por SARS COV-2 / COVID 19 en establecimientos de atención de la salud. 2020.
- Results publication: PubMed 32020029Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4. No abstract available.
- Results publication: PubMed 32150618Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Jul 28;71(15):732-739. doi: 10.1093/cid/ciaa237.
- Results publication: PubMed 27585965Mo Y, Fisher D. A review of treatment modalities for Middle East Respiratory Syndrome. J Antimicrob Chemother. 2016 Dec;71(12):3340-3350. doi: 10.1093/jac/dkw338. Epub 2016 Sep 1.
- Results publication: PubMed 32187464Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.
- Results publication: PubMed 32171740Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 May;55(5):105938. doi: 10.1016/j.ijantimicag.2020.105938. Epub 2020 Mar 12.
- Results publication: PubMed 15320751Romanelli F, Smith KM, Hoven AD. Chloroquine and hydroxychloroquine as inhibitors of human immunodeficiency virus (HIV-1) activity. Curr Pharm Des. 2004;10(21):2643-8. doi: 10.2174/1381612043383791.
- Results publication: PubMed 23208422Yan Y, Zou Z, Sun Y, Li X, Xu KF, Wei Y, Jin N, Jiang C. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013 Feb;23(2):300-2. doi: 10.1038/cr.2012.165. Epub 2012 Dec 4. No abstract available.
- Individual participant dataSharing planned: Yes. Communicating trial results and data to be able to combine data from multiple studies (live SR)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hernando Gaitán, MD principal investigator
Universidad Nacional de Colombia
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Emtricitabine/tenofovir, Colchicine Pill and Rosuvastatin in people with COVID-19, run by Universidad Nacional de Colombia at 6 sites in Colombia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 37 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Colombia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: Post-intervention at day 28). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04359095, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Aug 2021.