DOI: 10.5061/dryad.qjq2bvqf6
title: Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial

description: Objective: We evaluated whether ivermectin combined with doxycycline
 reduced the time to clinical recovery in adults with COVID-19 infection.
 Methods: This was a randomized, blinded, placebo-controlled trial in
 patients with mild-to-moderate COVID-19 symptoms randomly assigned to
 treatment (n = 200) and placebo groups (n = 200). The primary outcome was
 duration from treatment to clinical recovery. Secondary outcomes included
 disease progression and persistent COVID-19 positivity by RT-PCR. Results:
 Among 556 screened patients, 400 were enrolled and 363 completed
 follow-up. The mean patient age was 40 years, and 59% were men. The median
 recovery time was 7 (4–10) and 9 (5–12) days in the treatment and placebo
 groups, respectively (hazard ratio, 0.73; 95% confidence interval,
 0.60–0.90). The number of patients who recovered within 7 days was 61% and
 44% in the treatment and placebo groups, respectively (hazard ratio, 0.06;
 95% confidence interval, 0.04–0.09). The proportion of patients who
 remained RT-PCR positive on day 14 and whose disease did not progress was
 significantly lower in the treatment group than in the placebo group.
 Conclusions: Patients with mild-to-moderate COVID-19 infection treated
 with ivermectin plus doxycycline recovered earlier, were less likely to
 progress to more serious disease, and were more likely to be COVID-19
 negative by RT-PCR on day 14.
description: <b><i>Patients
 </i></b> Patients were enrolled between 1
 June 2020 and 30 August 2020. The inclusion criteria for enrollment were
 as follows: age greater than 18 years, positive COVID-19 RT-PCR test
 within 3 days prior to enrollment, and mild to moderately severe COVID-19
 infection. Patients who were unable to receive oral medications, were
 pregnant or breastfeeding, had severe COVID-19 symptoms (defined as
 tachypnea [&gt;30 breaths/minute] and hypoxia [SpO2 &lt; 90%] at
 room air and requiring supplemental oxygen), were admitted to intensive
 care or high-dependency units, or had known hypersensitivities to
 ivermectin or doxycycline were excluded from participation.
 <b><i>Trial
 design </i></b> This was an
 investigator-initiated, placebo-controlled trial. The independent data
 safety monitoring board of Dhaka Medical College monitored treatment
 safety and efficacy. Routine investigations were performed at the
 pathology laboratory of Dhaka Medical College. RT-PCR tests were performed
 at the virology laboratory of Dhaka Medical College and Bangabandhu Sheikh
 Mujib Medical University. Ivermectin, doxycycline, and placebo
 preparations were provided by a popular pharmaceutical company.
 Eligible patients were randomly
 assigned to the treatment group or the placebo group at a 1:1 ratio on day
 1 of the trial. Group assignment was not stratified according to disease
 severity. The allocation schedule was
 created with a list of random numbers generated using a random number
 generator program by the head of the Department of Medicine of Dhaka
 Medical College. Group assignment was concealed in sequentially numbered,
 opaque, sealed envelopes. The randomization code was maintained by the
 pharmaceutical company. Both the investigators and the patients were
 blinded to the treatment allocation. Decoding was performed at the end
 of the trial under the supervision of the principal of the
 institute. The trial was conducted in
 accordance with the principles of the Declaration of Helsinki and Good
 Clinical Practice guidelines, and was approved by the ethical review
 committee of Dhaka Medical College Hospital (ERC-DMC/ECC/2020/117). Dhaka
 Medical College is the largest tertiary care teaching hospital and the
 largest COVID-19 treatment hospital in Bangladesh. The trial was
 registered retrospectively at ClinicalTrials.gov (identifier:
 NCT04523831). Written informed consent was obtained from all patients
 prior to participation. The study is reported according to the Equator
 Network Guidelines. <b><i>Study
 interventions </i></b> The
 treatment group received a single dose of ivermectin 12 mg and doxycycline
 100 mg, twice daily for 5 days, in addition to standard of care. Standard
 of care included administration of paracetamol, antihistamines, cough
 suppressants, vitamins, oxygen therapy according to indication and need,
 low molecular weight heparin according to indication, appropriate other
 broad-spectrum antibiotics, remdesivir injection, other antiviral drugs,
 and other drugs for associated comorbid conditions. The placebo group received
 placebo in addition to standard of care. <b><i>Experimental
 procedures </i></b> The baseline demographic and
 clinical characteristics of patients were recorded. The date of random
 assignment was considered as day 1, and all patients received their
 initial study intervention on day 1. Outpatients were followed daily until
 at least 3 days of clinical recovery were observed. Clinical recovery was
 defined as a normal body temperature of 36.1C to 37.2C maintained for at
 least 3 days, significantly improved respiratory symptoms (respiratory
 rate &lt; 25/minute, no dyspnea), and oxygen saturation greater than
 93% without assisted oxygen inhalation, as recommended by the World Health
 Organization and the national guidelines of Bangladesh. Hospitalized patients were
 followed from day 1 through day 14 or until discharge or clinical
 improvement, whichever occurred later. Clinical status and vital signs
 (including respiratory status) were recorded daily. Adverse events as
 defined by the Medical Dictionary for Regulatory Activities (MedDRA) were
 documented. Laboratory tests were
 performed on day 1, and included the following: complete blood count,
 random blood glucose, creatinine, alanine transaminase, C-reactive
 protein, ferritin, and D-dimer. Chest radiography or chest CT scanning
 were performed as needed. For outpatients, test results were documented at
 the next visit. Hospitalized patients were tested on days 1 and 7 and when
 ordered by the treating physicians. COVID-19 RT-PCR testing was performed
 14 days after the initial positive test in all patients.
 <b><i>Outcome
 measures </i></b> The primary outcome was the
 number of days required for clinical recovery from day 1. Clinical
 recovery was divided into three categories: early recovery within 7 days,
 intermediate recovery within 7 to 11 days, and late improvement requiring
 12 or more days for recovery. Secondary outcomes were disease progression
 through mild, moderate, severe, or death, and the proportion of patients
 who continued to test positive for COVID-19 on day 14. Adverse drug
 reactions (adverse events assumed to be caused by the study intervention)
 were also recorded. Mild disease was defined as symptoms of an upper
 respiratory tract viral infection, including mild fever, dry cough, sore
 throat, nasal congestion, headache, muscle pain, anosmia, and malaise.
 Moderate respiratory symptoms such as cough and shortness of breath were
 observed without signs of severe pneumonia. Severe disease included severe
 dyspnea, tachypnea (&gt; 30 breaths/minute), and hypoxia (SpO2
 &lt; 90% at room air). These classifications were according to the
 World Health Organization and national guidelines of Bangladesh. The
 co-investigators assessed the outcome, graded the disease, and documented
 adverse reactions. <b><i>Statistical
 methods </i></b> We sought to enroll as many
 patients as possible in a short time. As a result, a priori power
 calculations were not performed. Instead, 200 patients were enrolled in
 each group and it was assumed that 20% of patients in each group would be
 lost to follow-up. A post-hoc power calculation [2SD2 (Zα/2+ Zβ) 2/d2]14
 using a two-tailed test, an alpha level of 0.05, and SD 6 indicated that
 the enrollment of 141 patients in each group (170 before 20% attrition)
 would result in an 80% chance of detecting a 2-day difference in median
 recovery time. Intention-to-treat analysis was
 performed. The difference in median recovery time was determined using
 Kaplan–Meier analysis and a log-rank test. Details of patients who were
 lost to follow-up, had died, or had withdrawn from the trial due to
 adverse effects were censored on the final study day. Differences in the
 clinical improvement in the three disease categories were analyzed using
 logistic regression. Hazard ratios (HRs) were calculated using Cox
 regression analysis. Categorical variables are presented as n (%),
 normally distributed continuous variables as mean (standard deviation
 [SD]), and skewed continuous variables as median (interquartile range
 [IQR]). Subgroup
 analysis was performed using the logistic regression analysis. HRs were
 calculated using Cox regression analysis. Age group, sex, fever, cough,
 respiratory distress, hypertension, diabetes, and presence of any
 comorbidity were adjusted. Subgroups consisted of age (less than vs. more
 than 60 years), sex, presence or absence of any comorbidities, mild
 disease, moderate disease, hospital admission, and interval between
 disease onset and drug application interval (less than vs. more than 4
 days from the onset of the disease). A forest plot was constructed to
 evaluate differences in the primary outcome among the subgroups. No
 corrections were made for multiple comparisons. All tests were two-tailed
 and the alpha was set at 0.05. Data were analyzed using SPSS software,
 version 20 (Armonk, NY: IBM Corp, USA).
description: AUTHOR
 INFORMATION             A. Principal
 Investigator Contact Information                         Name:
 <b>Dr. Reaz Mahmud</b>                        
 Institution: Dhaka Medical College            
 Address: Assistant Professor, Department of Neurology, Dhaka
 Medical            
 College. Dhaka, Bangladesh. Phone-+8801912270803                         Email:
 reazdmc22@yahoo.com             B. Associate or
 Co-investigator Contact Information                         Name:
 <b>Dr. Md. Mujibur Rahman</b>                        
 Institution: Dhaka Medical College Hospital Address: Professor and Head, Department of Medicine, Dhaka Medical College Hospital, Dhaka. Bangladesh Phone-+8801711525406                         Email: mmrahman61@gmail.com             C. Alternate Contact Information                         Name: <b>Dr. Farhana Binte Monayem</b>                         Institution: Sarkari karmachari Hospital                         Address: Medical officer, Sarkari karmachari Hospital. Dhaka, Bangladesh                         Phone-+8801920155971.                         Email: farhanabintemonayem94947@gmail.com 3. Date of data collection: 2020/06/01 to 2020/08/25 4. Geographic location of data collection: COVID-19 unit, Dhaka Medical College, Dhaka, Bangladesh 5. Information about funding sources that supported the collection of the data: <b>Non-funded study</b> SHARING/ACCESS INFORMATION 1. Licenses/restrictions placed on the data: This work is licensed under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication license       2. Links to publications that cite or use the data: Dryad: DOI https://doi.org/10.5061/dryad.dv41ns1xk 3. Links to other publicly accessible locations of the data: None 4. Links/relationships to ancillary data sets: None 5. Was data derived from another source? No             A. If yes, list source(s): 6. Recommended citation for this dataset: Reaz, Mahmud et al. (2021), Association of ABO blood groups with presentation and outcomes of confirmed SARS CoV-2 infection: A prospective study in the largest COVID-19 dedicated hospital in Bangladesh, Dryad, Dataset, https://doi.org/10.5061/dryad.dv41ns1xk DATA & FILE OVERVIEW 1. File List: Data set in SPSS 2. Relationship between files, if important: 3. Additional related data collected that was not included in the current data package: 4. Are there multiple versions of the dataset? No             A. If yes, name of file(s) that was updated:                         i. Why was the file updated?                         ii. When was the file updated? METHODOLOGICAL INFORMATION 1. Description of methods used for collection/generation of data: The manuscript has been accepted by PLOS ONE. DOI-10.1371/journal.pone.0249252 2. Methods for processing the data: This single-center prospective cohort study was conducted to evaluate the association of the ABO blood groups with the presentation and outcomes of confirmed COVID -19 infections in hospitalized and outdoor patients with COVID-19. The outcomes in this research included: A. Duration required for clinical improvement, as defined below; B. Proportion of patients converted to the next level of severity; C. Proportion of the patients remaining positive for RT-PCR of COVID-19 on day 14 after the initial positivity; D. Development of post-COVID syndrome as defined below. The recruitment was limited to patients who were more than 18 years of age with confirmed COVID-19 (RT-PCR positive) infection. Patients with hemoglobinopathies or other blood disorders were excluded from the study. Written informed consent was obtained from all the patients. Ethical approval was obtained from the ethical review committee of the institute. For the estimation, we grouped A positive and A negative blood groups into group I and other blood groups, such as B, AB, and O, irrespective of their Rh status, into group II. An assumption that the expected proportions to be cured from COVID-19 by day 12 in group I (blood group A) and group II (blood groups B, O, AB) are 0.70 and 0.90, respectively. Thus, we required a total of 378 samples at a 1:2 ratio, which would provide a power of at least 90% in two-tailed tests and a p value less than 0.05, to detect significant differences between the groups. Therefore, considering a 10% dropout rate, we needed 416 samples in total. <b>Procedure</b> A case record form was constructed to collect baseline information, such as demographics, blood groups, clinical signs and symptoms, comorbidities, and oxygen saturation. Routine investigations, including CBC, ESR, CRP, creatinine, RBS, SGPT, chest X-ray, and D-dimer were advised on enrollment. Real-time-polymerase chain reaction testing for COVID-19 was performed 14 days after the initial positive test in all patients. The patients were followed up directly or over the telephone with at least three-day intervals up to 30 days from the onset of the disease. 3. Instrument- or software-specific information needed to interpret the data: The data were analyzed using STATA version-15.1, StataCorp, 4905 Lakeway Drive, College Station, Texas 77845 USA 4. Standards and calibration information, if appropriate: 5. Environmental/experimental conditions: 6. Describe any quality-assurance procedures performed on the data: 7. People involved with sample collection, processing, analysis and/or submission: <b>Principal investigator and Co-investigators of the study</b> DATA-SPECIFIC INFORMATION: 1. Number of variables: 35 2. Number of cases/rows: 438 3. Variable List:  Age group of the patients: 1=&lt;40 years, 2=40-60 years, 3=&gt;60 years Gender: male -1or female-0 Fever: presence-1 or absence-0 Cough: presence-1 or absence-0 Running nose: presence-1 or absence-0 Respiratory distress: presence-1 or absence-0 Sore throat: presence-1 or absence-0 Hoarseness of voice: presence-1 or absence-0 Chest pain: presence-1 or absence-0 Diarrhea: presence-1 or absence-0 Vomiting: presence-1 or absence-0 Anorexia: presence-1 or absence-0 Anosmia: presence-1 or absence-0 Headache: presence-1 or absence-0 Lethargy: presence-1 or absence-0 Conjunctivitis: presence-1 or absence-0 Body ache: presence-1 or absence-0 Total duration of illness: duration required to have clinical recovery Conversion to next level of severity: presence-1 or absence-0 Persistent positivity: presence-1 or absence-0 Post Covid syndrome: presence-1 or absence-0 Neursthaenia: presence-1 or absence-0 Blood group: A positive, A negative, B positive, B negative, O positive, O negative, AB positive, AB negative Co-morbidity: presence-1 or absence-0 Diabetes: presence-1 or absence-0 Hypertension presence-1 or absence-0 Others: Severity of illness: Mild and moderate Response within 7 days: Yes -1 No-0 Response after 12 days; Yes-1 No -0 Ultimate severity: At the end Mild moderate and severe Rh exclusion: Only ABO blood group irrespective of Rh phenotype Comorbidity single: mere presence or absence of any co-morbidity A and non A: Group A: A positive, A negative, Non A: B negative, O positive, O negative, AB positive, AB negative Outcome death or alive: 4. Missing data codes: 99, 98 etc <b>Clinical Recovery:</b> <b>Clinical improvement or recovery</b> in patients was assessed according to the improvement criteria of the WHO and Bangladesh guidelines which required that the body temperature remained normal for at least 3 days, respiratory symptoms were significantly improved (respiratory rate &lt; 25 and no dyspnea), and SpO<sub>2</sub> &gt;93% was achieved without assisted oxygen inhalation. Respiratory distress; Shortness of breath, respiratory rate &gt;25/min, or oxygen saturation &lt;93% Severity of the disease:   <b>Mild disease</b> was defined as the symptoms of an upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, anosmia, or malaise. <b>Moderate disease</b>, including respiratory symptoms, such as cough and shortness of breath are present without signs of severe pneumonia.  <b>Severe disease</b> included severe dyspnea, tachypnea (&gt; 30 breaths/min), and hypoxia (SpO<sub>2</sub> &lt; 90% in room air). These classifications were made according to the World Health Organization and national guidelines of Bangladesh. In this study, we assessed the proportion of patients with <b>early recovery</b> (clinical improvement within 7 days of symptom onset), <b>late recovery</b> (clinical improvement required ≥12 days), <b>Severity conversion</b> (patients progress to more serious disease), <b>Persistently positive</b> for RT-PCR of COVID-19 (positive RT-PCR on a 14 day test), and <b> </b><b>Post-COVID syndrome</b> (in the absence of any definition, we defined it as 1. Persistence of illness with signs and symptoms beyond virologic clearance 2. Development of new symptoms within 1 month after the initial clinical and virologic cure, the etiology of which is postulated to be viral infection.