effects of ivermectin azithromycin cholecalciferol combined therapy on covid19 infected patients a proof of concept study
Abstract
As the world faces COVID-19, the search for effective treatments against the disease and its complications has turned its gaze to drugs that are classically used in other infectious diseases. Some drugs are being examined for the recent evidence on its effects on viral replication and inflammation. The aim of the study was to assess the outcome of Ivermectin-Azithromycin-Cholecalciferol combination therapy on early stages (I-IIa) of COVID-19 patients. This proof of concept study was carried out on confirmed COVID-19 patients in Mexico City, from April 01 to April 20, 2020. Patients who met inclusion criteria were invited to take Ivermectin (6 mg once daily in day 0,1,7 and 8) plus Azithromycin (500 mg once daily for 4 days) plus Cholecalciferol (4000 UI twice daily for 30 days). Treatment outcome was evaluated on the 10th day onward from the first day of the drug intake. Recovery rate of the 28 patients that received the combination therapy was 100%, the mean symptomatic recovery duration was 3.6 days and negative PCR was confirmed on day 10. Imaging findings of patients with pneumonia were improved on day 10. Transient and mild degree of adverse effect like diarrhea and nausea was noted by 3 (10.7%) patients. This study found that the combination treatment might mitigate disease progression without significant adverse effects. Further studies are needed in order to extrapolate these findings to moderate and severe COVID-19.
ntroduction
Currently, the world is in a race against time to curb the human and economic losses for which the SARS-Cov-2 virus is responsible. This virus infection was initially classified as pneumonia of unknown origin to be later recognized as COVID-19 []. The symptoms of COVID-19 infection appear after an incubation period of approximately 5 days with a median of 14 days to develop complications and death []. The progression depends on age and comorbidities, where a higher speed of progression is observed in patients>70-years old []. The spectrum of symptoms includes fever, cough, headache, diarrhea, dyspnea, anosmia and dysgeusia. Imaging studies reveal findings of pneumonia with grand-glass opacities, acute respiratory distress syndrome and acute cardiac injury [].
Scientists around the world are actively exploring drugs that could be potentially effective in combating COVID-19. Recent publications have drawn attention to the possible benefits of ivermectin, azithromycin and cholecalciferol. These drugs have been used for the treatment for infectious diseases since they have anti-inflammatory and antiviral properties []. The in vitro antiviral activity of Ivermectin has been related to inhibition of IMPα/1-mediated nuclear import of viral proteins []. The effect of azithromycin may be due to its properties as a weak base that could potentially block endocytosis and thereby limiting viral replication, by amplifying host ’ s interferon (IFN) pathway or by interfering with the SARS-CoV- 2 spike protein and host receptor ACE2 (angiotensin converting enzyme-2) interaction inhibiting viral entry into the cells []. On the other hand, in viral infections, cholecalciferol may decrease pro-inflammatory cytokines associated with the Th1 type response and increase anti-inflammatory cytokines associated with the Th2 type immune response []. Therefore, we decided to evaluate the efficacy of the Ivermectin- Azithromycin-Cholecalciferol combination and compare it to the standard therapy provided to patients in early stages of COVID-19.
Materials and Methods
Eligibility criteria
Eligible subjects were; 18 years old and older with a laboratory confirmed diagnosis of SARS-CoV2 using the CDC reverse transcription–polymerase chain reaction SARS-CoV-2 assay, with mild (cough, fever, malaise, myalgias, gastrointestinal symptoms, ageusia and anosmia) or moderate (dyspnea, tachypnea, hypoxemia, and abnormal lung findings) COVID-19 symptomatology. Patients with severe comorbid conditions like severe Bronchial asthma, COPD, severe ischemic heart disease, uncontrolled diabetes mellitus, advanced renal and hepatic disease, carcinoma, immuno-compromised or allergic to any of the drugs treatment were not included in this study. The flow chart (Figure 1) presents patients distribution.
Study design
This was a proof-of-concept study for the evaluation of clinical efficacy of Ivermectin, Azithromycin and Cholecalciferol combination in the treatment of new coronavirus (COVID-19). 35 adult patients who were tested positive for SARS-CoV-2 infection by RT PCR were included. The study was conducted in Mexico City, between April 1 and May 20, 2020. For the study purpose patients are presented as follows: Patients were voluntarily allocated into 2 groups at a 4:1 ratio; 1) Combination group (n=28): Ivermectin (6 mg once daily in day 0,1,7 and 8) plus Azithromycin (500 mg once daily for 4 days) plus Cholecalciferol (4000 UI twice daily for 30 days) plus standard treatment and 2) Control group (n=7): Standard treatment (self-isolation, proper nutrition, oral hydration and acetaminophen). Subjects enrolled in this study were treated as outpatients and received information about the correct use of medication and were kept informed about the course of their disease. They were instructed when to look for help in case of worsening of symptoms or pulmonary deterioration as recorded by daily pulse oximeter oxygen saturation (SpO2) measurements (thrice a day). All patients provided written informed consent. The study was approved by the Institutional Committees of the ISSSTE and was conducted according to the principles of the Declaration of Helsinki. Data were collected and analyzed by the investigators. This study is reported in accordance with the EQUATOR Reporting Guidelines.
Outcomes
The primary end point was the efficacy of the combination therapy. A negative PCR was counted as treatment success. Secondary end points included the duration from the first-day drug intake to the alleviation of clinically significant symptoms of COVID-19, temperature and ventilatory responsiveness. Regular contacts were maintained to find out the adverse or side effects of the therapy. Patients with pneumonia in the combination group (13 of 16) were tested for laboratory changes in D-dimer and ferritin comparing before and after treatment to analyse changes related to hypercoagulability and inflammation.
Statistical analysis
Data was expressed as mean ± SD for continuous variables and percentage for categorical variables description. Descriptive statistics were used for demographic and clinical data. We used paired-t test with Welch correction to compare means for intragroup analysis. Statistical significance was considered when p 0.05. Analyses were performed with Graph Pad Prism, v7.0.
Results
Characteristics
Basal clinical characteristics of patients are presented in Table 1. An overall mean of 45 ± 10 years of age. Obesity (34%) was the most frequent comorbidity. Acetaminophen was prescribed for all patients for temperature control; however, the frequency of use was only of 28.6% and 42.8% in the combination and control groups, respectively.
Chest-radiography findings of a patient in the Combination group before treatment. (B) Chest-radiography findings of a patient in the Combination group after treatment. (C) Computed tomography findings of a patient in the Combination group before treatment. (D) Computed tomography findings of a patient in the Combination group after treatment.
Oxygen saturation (SpO2) before and after for the Combination group. (B) Oxygen saturation (SpO2) before and after for the Control group. (C) Oxygenation index (SpO2/FiO2) before and after for the Combination group. (D) Oxygenation index (SpO2/ FiO2) before and after for the Control group.
Temperature measurement before and after for the Combination group. (B) Temperature measurement before and after for the Control group. (C) Symptomatology duration in days for the Combination and Control group.
Conclusion
This study has limitations, including its small sample size; due to its outpatient design, laboratories and CT-scans, to limit contact with reference COVID-19 hospitals, were not obtained from all patients. Radiologic and complete efficacy data will be presented later. In conclusion, in this study, a combined therapy with Ivermectin-Azithromycin-Cholecalciferol given for 7 days was effective to reduce symptomatology duration and clinical progression of COVID-19.
Credited to Biomedical Research