Clinical trial NCT04343092
Conditions: COVID 19
Sponsor: University of Baghdad
Start date: 2020-04-18; Completion date: 2020-06-01
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Comparing the effectiveness of Ivermectin( IVM) +Hydroxychloroquin + azithromycin (AZT) group to Hydroxychloroquin (HCQ) + azithromycin (AZT)

Detailed description:
Comparing effectiveness of single dose 0.2mg/kg Ivermectin (IVM) plus hydroxychloroquine (HCQ) 400mg BID in first day then 200mg BID for 5 days plus azithromycin (AZT) 500mg in first day then 250mg for 5 days.

The comparison group was a historical control population and data collected from the current study were compared to that historical control population

Arms: arm 1: Ivermectin 12 mg /weekly )+ Hydroxychloroquine 400mg/daily + azithromycin 500mg daily
Interventions: intervention 1: Ivermectin (IVM)
Intervention descriptions: intervention 1: Ivermectin 0.2 mg /kg (single dose at once =2 tablets of 6mg/weekly

Protocol documents:
Prot_SAP_000.pdf: 
Cover Letter 
 
Effectiveness of Ivermectin as add-on Therapy in COVID-19 Management 
ID: PRO20040001 
NCT04343092 
Date of Document July 15, 2020  
 
Last updated document July 15, 2020
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Introduction 
A novel coronavirus, severe acute respiratory syndrome  coronavirus 2 (SARS-CoV-
2), was first identified in December 2019 as the cause of a respiratory illness 
designated coronavirus disease 2019, or Covid-19  with significant public health 
impact (1). Several therapeutic agents have been evaluated for the treatment of 
Covid-19, however, none have yet been shown to be effective (2,3) 
Recently some reports on HCQ  [4-6], Azithromycin [7]  and Ivermectin [8] have 
shown therapeutic effects against novel coronavirus infection. 
Ivermectin is  an antiparasitic drug with a broad spectrum antiviral effect (9). 
Recently,  in vitro study showed reduction of viral RNA in Vero-hSLAM cells 2 
hours postinfection with SARS-CoV-2 clinical isolate Australia/VIC01/2020 (8). 
The authors hypothesized that the effect was likely due to the inhibition of IMP 
α/β1- mediated nuclear import of viral proteins.  
Because of the broad spectral antiviral activities of IVM and it is safety 
profile, It may offer a therapeutic potential to COVID-19. This study was designed 
to assess effectiveness and safety of add-on use of IVM to HCQ and AZT in COVID 
19 patients. 
 
Patients and Methods 
Study design  
This pilot interventional  single center study with a synthetic controlled arm (SCA) 
was conducted at Al-Shifa’a Hospital Center from  first of April to the end of May 
2020. Synthetic controlled arm was used due to difficulty of using placebo for our 
patients and the strong preference for the investigational product in this pandemic 
Covid-19 disease to improve drug development and reduce patients burden. SCA is 
an external control constructed from patient-level data from previous patients 
records to match the baseline characteristics of the patients in an investigational 
group and augment a single-arm trial to estimate treatment effects.  The SCA in this 


trial included previous patients who were treated by HCQ and AZT according to the 
Iraqi Ministry of Health protocols for treatment of covid-19.  
Ethical approval of the study was taken in accordance with the Declaration of 
Helsinki and its amendments and the Guidelines for Good Clinical Practices issued 
by the Committee of Propriety Medicinal Product of the European Union from Iraqi 
ministry of health and the study was registered with No. 497 at April 2020.  Also, 
this study was registered in ClinicalTrials.gov website under identifier number: 
NCT04343092. Informed consent was obtained from the participants to admit the 
study. 
 
Participants 
Inclusion criteria 
Inclusion criteria were the following: 1) men and women  with age at least 18 years 
2) mild to moderate COVID-19 diagnosed by positive polymerase chain reaction 
(PCR) testing <=3 days from enrollment 3)Patient acceptance  and willingness  to 
comply with planned study procedures and  to complete the follow up. 4) hospital 
admission 5) no participation in other clinical trials, such as antiviral trials, during 
the study period. 6) Able to provide informed consent 
 
Mild and moderate COVID-19 were defined according to World Health 
Organization (WHO) interim guidance (16). Mild COVID-19 was defined as 
symptomatic patients meeting the case definition for COVID-19 without evidence 
of viral pneumonia or hypoxia. The symptoms included: fever, cough, fatigue, 
anorexia, shortness of breath, myalgias. Other non specific symptoms such as soar 
throat, nasal congestion, headache, diarrhea nausea, vomiting, loss of smell, loss of 
taste, Older people and immunosuppressed patients in particular may present with 
atypical symptoms such as fatigue, reduced alertness, reduced mobility, diarrhea, 
loss of appetite, delirium, and absence of fever. Moderate COVID-19: included 
adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnea, fast 
breathing) but no signs of  severe pneumonia, including SpO2 ≥ 90% on room air. 
 
 
 
Exclusion criteria 
Exclusion criteria were the following: 1) severe COVID-19 defined as 
respiratory distress (≥30 breaths/min; in resting state, oxygen saturation of 93% or 
less on room air; or arterial partial pressure of oxygen (PaO2)/fraction of inspired 
oxygen (FIO2) of 300 or less. 2) Life threatening COVID-19 was defined as 


respiratory failure requiring mechanical ventilation; shock; or other organ failure 
(apart from lung) requiring intensive care unit (ICU) monitoring. 3) hypersensitivity 
or severe adverse events to IVM,  4) Alanine Aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 5 X upper limit of normal (ULN) 4)  pregnancy  5) breast 
feeding. 
6) history of severe asthma. 
Intervention 
Patients received IVM 200 Mcg single dose at the admission day as add on therapy 
to Iraqi Ministry of Health protocol for treatment of mild to moderate COVID-19 [ 
HCQ 400mg BID for the first day then 200mg BID for 5 days  plus AZT  500mg  
single dose in the first day then 250mg for 5 days]. We evaluated  these patients  for 
cure by clinical assessment and PCR swab testing. Nasopharyngeal or oropharyngeal 
swabs specimens were collected on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 , and 23  
for viral RNA detection and quantification till two successive days of negative PCR 
swab testing at least 24hrours apart. Virological testing was done at Alshifa’a 
Hospital Laboratory Center using  ABI  7500Dx Real-Time PCR System 
instruments (Applied Biosystems), USA. 
 
Outcomes 
The primary outcome was percentage of the cured patients within 23 days. Cure of 
the patients was defined by assessing  proportion of patients who were  symptoms 
free to be discharged from the hospital and included body temperature returned to 
normal for longer than 3 days, respiratory symptoms significantly improved, and 2 
consecutive negative PCR test results from nasopharyngeal swabs at least 24 hours 
apart. The secondary outcomes were time to cure in both groups. Time to cure is 
evaluated  by measuring time from admission of the patient to the hospital till 
discharge after being free of symptoms and negative PCR swab. Once 
nasopharyngeal and oropharyngeal swab viral PCR testing yielded negative results 
2 times consecutively, no further testing was performed. Also safety outcomes 
included treatment-emergent adverse events, serious adverse events, and premature 
discontinuations of study were recorded if present. 
 
Sampling method and sample size calculation 
A convenient consecutive sample of patients were enrolled in the study. The sample 
size calculated for this pilot trial was 30 patients : 15 in the active arm ( IVM group) 
and 15 in the controls (SCA) according to pilot study sample size rule of thumb to 
get medium effect size of 0.3 ≤ δ/σ < 0.7  with a statistical power of 90%. (17) 


 
 
Statistical analysis 
Statistical analysis was done using R packages software for IOS. The normality of 
continuous variables was analyzed using Shapiro Wilk test. Continuous variables 
were expressed as mean ± standard deviation (SD) if were normally distributed and 
median (interquartile range) if not normally distributed. Categorical variables were 
presented as number and percentages. Difference between normally distributed 
continuous variables was measured using Student’s t-test and Mann-Whitney U test 
if not normally distributed. Difference between categorical variables was evaluated 
by Chi square test. Effect size  for non normally distributed variables was measured   
using Vargha and Delany A  test. Kaplan Meier survival curve analysis with and log 
rank testing was used. The standardized mean difference effect size is small if value 
0.2- 0.5; medium if value 0.5-0.8, and large effect size if value 0.8-1.4 P value less 
than 0.05 was considered statistically significant.  
 
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