"A comparative study on Ivermectin- Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients".

Abstract

Coronavirus disease 2019 (COVID19) is a WHO declared a global pandemic. From the time of origin to till many antiviral and other drugs are on desperate use to find a cure. We decided to investigate the efficacy of Ivermectin-Doxycycline combination therapy and compare it to the standard HCQ-Azithromycin therapy among the mild to moderate cases of COVID19 patients in Bangladesh.
Patients were divided into two groups. Ivermectin 200µgm/kg single dose + Doxycycline 100mg BID for 10d and Hydroxychloroquine 400mg 1st day then 200mg BID for 9days + Azithromycin 500mg daily for 5Days was given to the Group-A and group-B respectively. Treatment outcomes were evaluated on the 5th day in case of asymptomatic patients and the 2nd non-symptomatic day onward from the first day of the drug intake by PCR study.
According to this study both the Ivermectin-Doxycycline and HCQ-Azithromycin treatment regimens were found to be effective against SARS-CoV-2 infection. But concerning the treatment outcome, adverse effect, and safety Ivermectin-Doxycycline combination is superior to HCQ-Azithromycin therapy for mild to moderate degree of COVID19 patients in Bangladesh. We strongly believe by rescheduling and increasing the duration of Ivermectin to 3days will certainly decrease the recovery period further than that of our study. This will also prevent disease progression and morbidity to COVID19 patients.

Full text

A Comparative Study on Ivermectin-Doxycycline and
Hydroxychloroquine-Azithromycin Therapy on
COVID-19 Patients
Coronavirus disease 2019 (COVID-19) is a global pan-
demic declared by the world health organization
(WHO). Over ninety million people have already been
infected by severe acute respiratory syndrome‐corona-
virus‐2 (SARS-CoV-2), and billions have been aected by
the socioeconomic squeal. As SARS-CoV-2 is a novel virus,
there are no proven treatment options yet. Early treatment
before the disease becomes severe would be optimal. The
Objectives: We investigated the outcomes of Ivermectin-Doxycycline vs. Hydroxychloroquine-Azithromycin combina-
tion therapy in mild to moderate COVID19 patients.
Methods: Patients were divided randomly into two groups: Ivermectin 200µgm/kg single dose + Doxycycline 100mg
BID for ten days in group A, and Hydroxychloroquine 400mg for the rst day, then 200mg BID for nine days + Azithro-
mycin 500mg daily for ve days in group B (Control group). RT-PCR for SARS-CoV-2 infection was repeated in all symp-
tomatic patients on the second day onward without symptoms. Repeat PCR was done every two days onward if the
result found positive. Time to the negative PCR and symptomatic recovery was measured for each group.
Results: All subjects in Group A reached a negative PCR, at a mean of 8.93 days, and reached symptomatic recovery, at a
mean of 5.93 days, with 55.10% symptom-free by the fth day. In group B, 96.36% reached a negative PCR at a mean of
9.33 days and were symptoms-free at 6.99 days. In group A 31.67% of patients expressed symptoms caused by medica-
tion, this was 46.43% in group B.
Conclusion: The combination therapy of Ivermectin-Doxycycline showed a trend towards superiority to the combina-
tion of Hydroxychloroquine-Azithromycin for mild to moderate COVID19 disease.
Keywords: Azithromycin, Bangladesh, COVID-19, Doxycycline, Hydroxychloroquine, Ivermectin, randomized controlled
trial (RCT)
Abu Taiub Mohammed Mohiuddin Chowdhury,1 Mohammad Shahbaz,2 Md Rezaul Karim,3 Jahirul Islam,
Guo Dan,1 Shuixiang He1
1Department of Gastroenterology, First Aliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
2Chakoria Upazilla Health Complex, Cox’s Bazar, Bangladesh
3Biomedical Research Institute of Hubei University of Medicine, Shiyan, China
4Department of Epidemiology and Health Statistics, Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China
Abstract
DOI: 10.14744/ejmo.2021.16263
EJMO 2021;5(1):63–70
Research Article
Cite This Article: Mohiuddin Chowdhury ATM, Shahbaz M, Karim MR, Islam J, Dan G, He S. A Comparative Study on Ivermec-
tin-Doxycycline and Hydroxychloroquine-Azithromycin Therapy on COVID-19 Patients. EJMO 2021;5(1):63–70.
Address for correspondence: Shuixiang He, MD; PhD. Department of Gastroenterology, First aliated hospital of Xi’an Jiaotong University,
Xi’an, Shaanxi, P.R. China
Phone: 008613991380928 Email: dyyyjxk@xjtu.edu.cn
Abu Taiub Mohammed Mohiuddin Chowdhury, MD. Department of Gastroenterology, First Aliated Hospital of Xi’an Jiaotong University,
Xi’an, Shaanxi, P.R. China
Phone: 008801817711079; 008615529366232 E-mail: dr_mohiuddinchy@yahoo.com
Submitted Date: January 21, 2021 Accepted Date: February 15, 2021 Available Online Date: February 25, 2021
©Copyright 2021 by Eurasian Journal of Medicine and Oncology - Available online at www.ejmo.org
OPEN ACCESS This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

64 Chowdhury et al., A Comparative Study on Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin Therapy on COVID19 Patients. / doi: 10.14744/ejmo.2021.16263
treatment's current considerations include lopinavir/ri-
tonavir, favipiravir, and remdesivir. These are currently in
use in moderate to severe COVID-19 patients. Treatments
for patients in the early stage of the disease with mild
to moderate symptoms have not been well established.
Studies have shown that Chloroquine and Hydroxychlo-
roquine (HCQ) are not benecial in moderate to severe
COVID19 disease. However, they have become the current
standard for mild to moderate and early disease states.
Chloroquine has been shown as a potential suppressor of
SARS-CoV-2 in an in vitro study.[1] Though many trials have
established a good outcome in mild to moderate cases,
unfortunately, chloroquine toxicity is a paramount con-
cern.[2] HCQ, a less toxic derivative, has also been found to
be eective.[3] Recently, an anti-parasitic drug Ivermectin
has been described as highly eective in an in vitro study
against SARS-CoV-2.[4] HCQ-Azithromycin combination
therapy has also been shown to be a possibly eective
combination therapy in the treatment of SARS-CoV-2.[5,
6] These two studies reported 100% and 83% recovery in
the sixth and seventh day with a reduced hospital stay.
Alam MT et al.[31] recently described an encouraging result
in a case series of COVID19 patients with a combination of
Ivermectin and Doxycycline. Till now, there has not been
a randomized study of Ivermectin in patients with mild
to moderate COVID19. Ivermectin is well-tolerated, less
toxic, and has fewer adverse eects than HCQ. HCQ-Azi-
thromycin combination therapy has also been mentioned
in the “National guideline for COVID management 4.0” of
Bangladesh as an initial therapy against COVID19. Due to
drug complications and discouraging statements about
HCQ treatment made by WHO, it is crucial to nd an eec-
tive, economical alternative to HCQ. Therefore, we decid-
ed to investigate the ecacy of Ivermectin-Doxycycline
combination therapy and compare it to the standard
HCQ-Azithromycin treatment according to the “National
guideline for COVID management 4.0” among the mild to
moderate cases of COVID19 patients.
Methods
Ethical Consideration and Approval,
Informed Consent
This study was approved by the Ethical committee of Cha-
koria Upazilla Health Complex, Chittagong, Bangladesh.
UHC/Chakoria/Ethical Approval/2020/01 (15-04-20). The
purpose of the research was explained to participants.
Once verbal consent was understood and agreed upon,
a written form was given. This was done to get informed
consent and legal identication. The individuals who gave
consent were enrolled in this study.
Study Population and Data Collection
Patients (16 years to 80 years of age) tested positive for
SARS-CoV-2 infection by Real-time polymerase chain reac-
tion (RT-PCR) at Chakoria Upazilla Health Complex, Cox's
Bazar, Bangladesh, from second may to the fth June 2020,
were initially included in this study, including those with
and without the symptoms. The PCR analysis of the collect-
ed samples was performed in Cox's Bazar Medical College.
All patients received a full evaluation, including a history
of current illness, comorbid condition, and associated com-
plaints. Patients with unstable comorbid conditions like
bronchial asthma, chronic obstructive pulmonary disease
(COPD), ischemic heart disease (IHD), uncontrolled dia-
betes mellitus (DM), advanced renal and hepatic disease,
carcinoma, hospitalized, and immuno-compromised pa-
tients were excluded. Patients were examined for oxygen
saturation and only those with oxygen saturation of 95%
or above who t the outpatient treatment protocol for
COVID19 were included. Patients with respiratory symp-
toms received chest radiographs. Those with normal or
near-normal chest radiographs (up to 10% involvement)
were included.
Randomization and Treatment Intervention
Randomization was done using an odd-even methodolo-
gy and applied to registration numbers, consecutively in a
1:1 ratio, by the hospital registration oce. Treatment was
given, and the nal enrolment was done by the attending
physician (investigator). All the patients enrolled in this
study were treated as outpatient department (OPD) pa-
tients.
For the study, patients were divided into two groups, as fol-
lows:
• Group A (n=60): Ivermectin 200µgm/kg single dose +
Doxycycline 100mg BID for ten days.
• Group B (n=56): Hydroxychloroquine 400mg for the
rst day, then 200mg BID for nine days + Azithromy-
cin 500mg daily for ve days (considered as the control
group).
Ivermectin dosing was determined by the case series per-
formed by Alam MT et al., and HCQ dosing was decided as
per "National guideline for COVID management 4.0".
All the subjects were provided with symptomatic treat-
ment such as fever, headache, cough, and myalgia. Drug
interactions and contraindications for each individual
were considered carefully. The schedule of medication
intake was adequately explained to each patient. Group
A's instructions included that Ivermectin tablet (200µg/
kg) single dose to be taken on an empty stomach an hour
before a meal on the rst day. Doxycycline 100 mg cap-

65
EJMO
sule be taken twice daily after meal for ten days starting
from day one. Group B's instructions included Hydroxy-
chloroquine 400mg (two tablets of 200mg each) to be
taken on the rst day, then 200mg (one tablet) twice daily
after meal for nine days. Azithromycin 500mg (one tablet
of 500mg) to be taken once daily after meal for ve days
starting from day one. Patients were advised to self-iso-
late, take proper nutrition, hydration, and maintain a san-
itary environment.
Repeat Nasopharyngeal and Throat Swab PCR
All subjects underwent repeat nasopharyngeal and throat
swab PCR for SARS-CoV2 every other day until their PCR
was negative. These repeat PCR tests began on the fth
day after taking the medication for subjects who began the
study and remained symptom-free. The PCR repeat testing
began on the second symptom-free day onward for sub-
jects who began the study with symptoms or developed
symptoms. The investigators had telephone contact with
all the subjects every three days throughout the study to
determine any therapy's adverse eects. A re-evaluation
PCR was performed after seven days following the rst
negative PCR.
Endpoints were a negative PCR and resolution of symp-
toms. The duration from the rst day of drug intake to the
negative PCR was counted as the recovery period. The du-
ration from the rst day of drug intake to the disappearance
of symptoms was counted as the period to symptomatic
recovery. "Adverse eects" were determined by the exis-
tence of the pharmacological side eects of the particular
drug during treatment. A detailed history of adverse ef-
fects (other than previous disease symptoms) experienced
by each participant was collected during the follow-up
sample collection. An asymptomatic participant presented
with no symptom of COVID-19 and remained the same un-
til the negative PCR.
Data Analysis and Statistics
Data were presented as mean±standard deviation, and sta-
tistical analysis was done by Graph pad Prism software. Col-
umn analysis was done to nd the mean with the standard
deviation in each group. T-test was done to see the signi-
cance between the values where needed. P<0.05 was con-
sidered statistically signicant.
Results
This study was completed in a pre-determined period
from May second to June fth, 2020, and 181 patients
tested positive for SARS-CoV-2 infection in that period.
42 patients had comorbid conditions (some required hos-
pitalization) that might have aected the recovery time,
and 14 patients were unwilling to participate in the study.
Nonetheless, 9 patients did not show-up (3 from group A
and 6 from group B) for the follow-up sample collection,
so these were excluded, and 116 patients were nally in-
cluded in the analysis (Fig. 3).
Demographic Characteristics of the Study Subjects
As shown in Table 1, the total number of patients was 116;
male 84 and female 26, age 16 to 80 years, and mean age
(33.94±14.12 years). Group A (Ivermectin + Doxycycline):
male 43 (71.67%), female 17 (28.33%), age 35.72±15.1 years;
males 37 years and female 32.88 years. Group B (Hydroxy-
chloroquine + Azithromycin): male 47 (83.93%), female 9
(16.07%), age 31.91 years; male 31.35, and female 34.5
years. (Fig. 1 a, b) Among the total, 91 (78.45%) were symp-
tomatic, and 25 (21.55%) were asymptomatic patients with
contact history. These were 49 (81.67%) and 11 (18.33%) in
group A, 42 (75%) and 14 (25%) in group B.
Recovery Rate and Mean Recovery Duration
Between Groups
In group A, recovery to negative PCR rate was 100% (60/60).
The mean recovery duration to negative PCR was 8.93 days
(8 to 13 days). 41 (63.3%) of patients had no new complaints
other than their presenting symptoms. New symptoms that
may have been attributed to adverse drug eects included
Table 1. Baseline characteristics of the study group patients.
Parameters
Number of patients (n) 116
Male 90 (77.58)
Female 26 (22.41)
Group A (n, %) 60
Group A Male (n, %) 43 (71.67)
Group A Female (n, %) 17 (28.33)
Group B (n) 56
Group B Male (n, %) 47 (83.93)
Group A Female (n, %) 9 (16.07)
Age (in years) 33.94±14.12 (8 to 80 Years)
Symptomatic (n, %) 91 (78.45)
Asymptomatic (n, %) 25 (21.55)
Agegroup A (in years) 35.72±15.1
Male 37.14±14.72
Female 32.88±16.2
Symptomatic (n, %) 49 (81.67)
Asymptomatic (n, %) 11 (18.33)
Agegroup B (in years) 31.91±12.72
Male 31.35±12.95
Female 34.5±11.74
Symptomatic (n, %) 42 (75)
Asymptomatic (n, %) 14 (25)

66 Chowdhury et al., A Comparative Study on Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin Therapy on COVID19 Patients. / doi: 10.14744/ejmo.2021.16263
lethargy in 14 (23.3%), nausea in 11 (18.3%), and occasional
vertigo in 7 (11.66%) of patients (Fig. 1c).
In group B, out of 56 patients, two male patients were re-
ferred to a tertiary hospital. They did not recover to a neg-
ative PCR as part of the study. Therefore, the recovery rate
to negative PCR was 96.36% (54/56). The mean duration of
recovery to negative PCR was 9.33 days (5 to 15 days). 30
(53.57%) of the patients had no new complaints other than
their presenting symptoms. Fresh symptoms that were rec-
ognized as an adverse eect of HCQ included 13(23.21%)
with mild blurred vision and headache; 22 (39.2%) with
increased lethargy and dizziness, 10 (17.85%) with occa-
sional, mild palpitation, and 9 (16.07%) with nausea and
vomiting (Fig. 1e).
Dierence in Recovery to Negative PCR
between Groups
The dierence between group A and group B recovery to
negative PCR duration was not statistically signicant in
unpaired t-test, p=0.2314 (Fig. 1c). Subgroup analysis of
the recovery duration: male 9.18±1.90 days and female
8.92±1.32 days, p=0.515; in group A male 8.907±1.342
days and female 9±1.173 days, p=0.44; and in group B male
9.18±1.90 days and female 8.92±1.32 days, p=0.407. The re-
covery duration of both group males and females were not
signicant, p=0.18 and 0.69, respectively (Fig. 1f).
The mean duration of symptomatic recovery was 5.93 days
(5 to 10 days) in group A and 6.99 days (4 to 12 days) in
group B (Fig. 1g). This dierence in time to symptomatic re-
covery between group A and group B is not statistically sig-
nicant, p=0.071 (Fig. 1g). In group A, over half of the sub-
jects had become symptom-free by ve days 27 (55.10%),
with the remaining subjects becoming symptom-free on
day six (16.32%), day seven (12.24%), day eight (8.16%),
day nine (4%), and day ten (2.04%) (Fig. 1h). In group B, re-
covery was slower with subjects becoming symptoms free
on fourth day 3 (7.14%), the fth day 10 (23.8%), sixth day
9 (21.43%), seventh day 8(19.04%), eighth & ninth day 4
(9.52% each), eleventh day 2 (4.76%), and tenth and twelfth
day (2.38% each) (Fig. 1h).
Mean Duration of Time to Negative PCR between
Groups
In the secondary analysis of subjects who began the study
with symptoms, the mean duration of time to negative
PCR was 9.061 days in group A and 9.738 days in group B.
This was not statistically signicant in the unpaired t-test,
p=0.0714. The mean duration of time to becoming nega-
tive PCR of patients without symptoms was 8.364 days in
group A and 7.917 days in group B, which was not statis-
tically signicant in unpaired t-test, p=0.443 (Fig. 2b). Fur-
ther analysis showed the highest recovery was achieved
on the eighth day among group A patients in case of both
asymptomatic (n=11) and symptomatic (n=49) patients,
Figure 1. (a) Number of patients according to gender among the
groups. (b) Gender variation of age among the study groups (data
presented as mean±SD). (c) Recover duration of Ivermectin-Doxy-
cycline and HCQ-Azithromycin group; note: the dierence between
the groups' recovery duration is not statistically signicant P=0.231.
(d) Adverse eect expressed by the patients of group A. (e) Adverse
eect experienced by the patients of group B. (f) Variation of the re-
covery duration according to the gender; note: males in group B and
males as gender, in general, have a longer recovery period than the
females. (g) Duration of the symptomatic recovery (in days) among
the groups. The dierence between the duration among groups is
not signicant P=0.071. (h) Subgroup analysis of the recovery dura-
tion among the groups. Note: group A has a higher number of symp-
tomatic recoveries in the early days; this indicates a better ecacy of
Ivermectin-Doxycycline therapy.
a
c
e
g
b
d
f
h

67
EJMO
8 (72.72%) and 22 (44.89%), respectively (Fig. 2 c, d). This
recovery was relatively slower in group B. On the sixth
day 3 (7.5%), seventh day 1 (2.5%), eighth day 9 (22.5%),
ninth and tenth day 8 (20%) each, eleventh and twelfth
day 4 (10%) each, thirteenth day 1 (2.5%), and fourteenth
day 2 (5%) in group B patients with symptoms (n=40).
Among asymptomatic patients (n=14), this was 1 (7.5%)
on the fth day, 2 (14.2%) individually on the sixth, sev-
enth, eighth, tenth day, 4 (28.57%) on the ninth day, and
1 (7.1%) on the eleventh day (Fig. 2 c, d). No signicant
dierence in the recovery duration was found in the sub-
group analysis of the recovery duration according to the
study groups' age. 61 to 70 years in group A had the lon-
gest recovery duration, 9.5±2.12, and 71 to 80 years was
the shortest 8days. In group B, this was 11.71±2.48 days in
the 41 to 50 years and 8.37±2.44 days in the 10 to 20 years
age group (Fig. 2 e).
Discussion
The COVID-19 pandemic in Bangladesh is part of the coro-
navirus worldwide pandemic disease caused by a newly
discovered coronavirus. It was initially called novel corona-
virus and later named SARS-CoV-2 due to its similar char-
acteristics with SARS-CoV-1.[7-9] The treatment methods
for COVID-19 are emerging and rapidly evolving because
of ongoing research being done worldwide by a record
number of investigators. Due to each medical and research
facility's uniqueness, the approach to patient care with
COVID-19 varies from institution to institution in Bangla-
desh. Many patients with mild to moderate disease were
treated with HCQ and Azithromycin. New concerns about
HCQ has led us to seek alternatives with shorter recovery
time and better tolerability. Thus, we have undertaken a
comparative therapeutic analysis, comparing these stan-
dard drugs with Ivermectin and Doxycycline.
In this randomized treatment study of groups A and B, the
presenting symptoms of the COVID19 patients were fever,
cough, sore throat, weakness, chest discomfort, breath-
Figure 2. (a) Comparison between the symptomatic recoveries
among the study groups. Note: group A (Ivermectin-Doxycycline)
showed a pick recovery on the 5th day. In group B (HCQ-Azithromy-
cin), the symptomatic recovery started relatively earlier on the 4th
day but had a slow trend. (b) The mean duration of recovery (be-
ginning of the treatment to the negative PCR) of the patients with
and without symptoms among groups A& B was not statistically
signicant in the subgroup analysis. (c) Subgroup analysis of recov-
ery duration of the symptomatic patients among the study groups.
Maximum numbers of negative PCR were achieved on the 8th day in
both groups. Group A 22 (44.89%) and group B 9 (22.5%). The recov-
ery rates are faster in group A, though relatively earlier but slow in
group B. (d) Subgroup analysis of the asymptomatic patients' recov-
ery duration. Most group A patients gained viral clearance on 8th day
8 (72.72%). Not: rst PCR was done on the 5th day. In group B, 1(7.1%)
was recovered on the 5th day and 2 (14.2%) on the 6th day. The highest
recovery was observed on the 9th day 4 (28.57%). (e) Subgroup com-
parison of the recovery duration according to age.
a
c
e
b
d
Figure 3. Flow diagram of randomization and treatment assignment
of the participants.

68 Chowdhury et al., A Comparative Study on Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin Therapy on COVID19 Patients. / doi: 10.14744/ejmo.2021.16263
ing diculty, diarrhea, myalgia, and abdominal pain. To
avoid the recovery duration's inuence, we solely selected
the cases devoid of severe comorbidities. The dierence
in recovery to negative PCR duration was not signicant
(p=0.231) among the two groups. The mean recovery dura-
tion is shorter, 8.933 days in group A than in group B, 9.33
days (Fig. 1 c). Also, group A had a better outcome ratio of
100% (60/60) recovery to negative PCR compared to that of
group B 96.36% (54/56).
HCQ has decades of treatment use as an immunomodula-
tor.[10] At present, it has been the topic of discussion con-
cerning its potential use to treat patients with COVID-19.[11]
It is thought that the eect of HCQ results in the selective
killing of the infected cells. Therefore, it may accelerate viral
clearance in COVID-19.[13] Some studies showed that severe
deterioration in some patients with COVID-19 had been
closely associated with dysregulated and excessive cyto-
kine release termed "cytokine storm."[14, 15] HCQ was found
to inhibit SARS-CoV-2 infection in vitro and signicantly de-
crease cytokine production, especially the pro-inamma-
tory cytokines.[16] Correspondingly, Azithromycin is a mac-
rolide group of antibiotics. It has been studied as part of
possible treatment of COVID-19 combined with HCQ and
has been reported to add benet.[17, 18] However, a recent
report failed to establish whether it has any antiviral activ-
ity or any synergistic activity with HCQ in the treatment of
COVID-19.[19] Therefore, a further comparative study can
enhance the signicance of HCQ- Azithromycincombina-
tion therapy.
On the other hand, Ivermectin is a relatively safe and
well-tolerated anti-parasitic drug that can inhibit nuclear
transport activity.[20] Recently, in-vitro studies have shown
its function against SARS-CoV-2.[21, 22] A recent report sug-
gested that Ivermectin reduces mortality rates in hospi-
talized patients with COVID-19.[23] However, it is unknown
if antiviral levels are attainable while using known dosing
regimens of Ivermectin therapy in patients with COVID-19.
[24, 25] Thus, it is vital to investigate Ivermectin's dose regi-
mens for COVID-19 treatment or to determine if there is
appropriate synergism using combination therapy with an-
other drug. Also, Doxycycline is a tetracycline class of anti-
biotics with a long history of clinical use.[26] The ecacy and
tolerability of Ivermectin and Doxycycline were established
in combination with an earlier study to treat onchocercia-
sis.[27] Several recent studies have suggested a therapeutic
role of Doxycycline against COVID-19.[28, 29]
In our study, the dierence in recovery to become symp-
tom-free was not statistically signicant (Fig. 1c). Never-
theless, the Ivermectin group showed better symptomatic
recovery than the HCQ group (Fig. 2 a-d). According to the
age among study groups, the dierence was not statisti-
cally signicant (Fig. 2 e). Ivermectin-Doxycycline combina-
tion expressed an earlier and faster relief of COVID features
(Fig. 1 g) and viral clearance than the HCQ-Azithromycin
combination. However, the mean recovery duration is not
statistically signicant (Fig. 1c). In the Ivermectin-Doxy-
cycline group a greater number of patients gained faster
symptomatic recovery than that of the HCQ group (Fig. 1h]
This suggests Ivermectin-Doxycycline may have better e-
cacy in reducing the COVID-19 symptoms than HCQ-Azith-
romycin therapy.
The Ivermectin-Doxycycline group had better patient
compliance and fewer adverse eects compared to the
HCQ-Azithromycin group (Fig. 1 d, e). The adverse eects
of HCQ in our study are similar to others.[30, 31] The sex dier-
ence was also examined, but there were no signicant dif-
ferences between males and females in this study (Fig. 1 f).
According to this study, the Ivermectin-Doxycycline treat-
ment regimen was well tolerated, and eective treatment
for mild to moderate degrees of SARS-CoV-2 infection. Not
only concerning the time to become symptom-free and
the viral clearance, but also in terms of safety, side-eect
prole, and compliance the Ivermectin-Doxycycline com-
bination is superior to HCQ-Azithromycin therapy for mild
to moderate degrees of COVID-19 patients. We strongly be-
lieve that increasing the dose and the duration of Ivermec-
tin treatment will further benet in reducing the recovery
period of COVID19 infection beyond that which was seen
in our study. This will also prevent disease progression and
morbidity in COVID-19 patients.
Our study has limitations, and these include relatively small
sample size, the dose of Ivermectin, and case selection. The
outcome may be biased by factors like disease severity, lack of
cooperation of some participants, and unknown comorbidity.
Conclusion
Researchers have suggested dierent drug combination
therapies for COVID19. According to our study, the Iver-
mectin-Doxycycline combination therapy has better symp-
tomatic relief, shortened recovery duration, fewer adverse
eects, and superior patient compliance compared to the
Hydroxychloroquine-Azithromycin combination. Based on
this study's outcomes, the Ivermectin-Doxycycline combi-
nation is a superior choice for treating patients with mild
to moderate COVID-19 disease. Despite this study's limita-
tion, we tried to select our study group patients without
any major or unstable comorbid condition as far as possi-
ble to avoid dierences in treatment outcomes among the
groups. Further study is required on a larger scale with an
increase in Ivermectin treatment duration.

69
EJMO
Disclosures
Acknowledgment: Alexis Lieberman, MD; Associate chief for
Ambulatory Pediatrics and Director of the Adolescent Program at
Albert Einstein Medical Center in Philadelphia, Pennsylvania, for
his kind assistance in editing this manuscript.
The authors are tankful to all the doctors and stas of the Chakoria
Upazilla Health Complex, Department of Gastroenterology-First
Aliated Hospital of Xi'an Jiaotong University, and to Ministry of
Health and Family welfare Bangladesh.
Other aliation of Abu Taiub Mohammed Mohiuddin Chowd-
hury: Ministry of Health and Family welfare Bangladesh.
Ethics Committee Approval: The study was approved by the
local ethical committee of Chakoria Upazilla Health Complex,
Cox's Bazar, Bangladesh. Approval no: UHC/Chakoria/Ethical
Approval/2020/01 (15-04-20).
Peer-review: Externally peer-reviewed.
Conict of Interest: None declared.
Authorship Contributions: Concept – A.T.M.M.C.; Design –
A.T.M.M.C.; Supervision – S.H.; Materials – M.R.K.; Data collection
&/or processing – A.T.M.M.C., J.I., G.D.; Analysis and/or interpreta-
tion – A.T.M.M.C. Literature search – M.R.K.; Writing – A.T.M.M.C.;
Critical review – S.H.
References
1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine
eectively inhibit the recently emerged novel Coronavirus
(2019‐nCoV) in vitro. Cell Res 2020;30:269‐271. [CrossRef]
2. Weniger H, Organization WH Review of side eects and
toxicity of chloroquine. 1979.https://apps.who.int/iris/han-
dle/10665/65773. Accessed March thirty-rst, 2020.
3. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and pro-
jection of optimized dosing design of Hydroxychloroquine for
the treatment of severe acute respiratory syndrome Coronavi-
rus 2 (SARS‐CoV‐2). Clin Infect Dis 2020. [CrossRef]
4. Caly L, Druce JD, Catton MG, Jans DA, Wagsta KM. The
FDA-approved drug ivermectin inhibits the replication of
SARS-CoV-2 in vitro. Antiviral Res 2020. [CrossRef]
5. Gautret P, Lagier J‐C, Parola P, et al. Hydroxychloroquine and
Azithromycin as a treatment of COVID‐19: results of an open‐
label non‐randomized clinical trial. Int J Antimicrob Agents
2020.
6. Gautret P, Lagier J‐C, Parola P, Hoang VT, Meddeb L, Sevestre J.
Clinical and microbiological eect of a combination of Hydroxy-
chloroquine and Azithromycin in 80 COVID‐19 patients with at
least a six‐day follow up: an observational study. Mediterr‐In-
fect.2020:101663 https://www.mediterranee-infection.com/
wp-content/uploads/2020/03/COVID-IHU-2-1.pdf [CrossRef]
7. Chan, Jasper F., et al. "A familial cluster of pneumonia associat-
ed with the 2019 novel coronavirus indicating person-to-per-
son transmission: a study of a family cluster." The Lancet, vol.
395, no. 10223, 2020, pp. 514-523. [CrossRef]
8. Li, Jinzhong, et al. "Clinical features of familial clustering in pa-
tients infected with 2019 novel coronavirus in Wuhan, China."
Virus Research, vol. 286, 2020, p. 198043. [CrossRef]
9. "Clinical ndings in a group of patients infected with the 2019
novel Coronavirus (SARS-Cov-2) outside of Wuhan, China: ret-
rospective case series." BMJ, 2020, p. m792. [CrossRef ]
10. Meyerowitz, Eric A., et al. "Rethinking the role of hydroxychlo-
roquine in the treatment of COVID‐19." The FASEB Journal, vol.
34, no. 5, 2020, pp., 6027-6037. [CrossRef]
11. Savarino, Andrea, and Mohammad Tarek. "Pharmacokinetic
bases of the hydroxychloroquine response in COVID-19: im-
plications for therapy and prevention." 2020.
12. Juurlink, David N. "Safety considerations with chloroquine,
hydroxychloroquine and azithromycin in the management of
SARS-CoV-2 infection." Canadian Medical Association Journal,
vol. 192, no. 17, 2020, pp. E450-E453. [CrossRef]
13. Accapezzato, Daniele, et al. "Chloroquine enhances human
CD8+ T cell responses against soluble antigens in vivo." Jour-
nal of Experimental Medicine 2005;202:6:817-828. [CrossRef]
14. Ye, Qing, et al. "The pathogenesis and treatment of the `Cyto-
kine Storm' in COVID-19." Journal of Infection 2020;80:6:607-
613. [CrossRef]
15. Mahmudpour, Mehdi, et al. "COVID-19 cytokine storm: The
anger of inammation." Cytokine 2020;155151. [CrossRef]
16. Liu, Jia, et al. "Hydroxychloroquine, a less toxic derivative of
chloroquine, is eective in inhibiting SARS-CoV-2 infection in
vitro." Cell Discovery, vol. 6, no. 1, 2020. [CrossRef]
17. Schaper, Charles. "A Mechanism of Action for Hydroxychlo-
roquine and Azithromycin to Inhibit Coronavirus Disease
COVID-19." 2020. [CrossRef]
18. Chen, Jun, et al. "COVID-19 infection: the China and Italy per-
spectives." Cell Death & Disease, vol. 11, no. 6, 2020. [CrossRef]
19. Molina, J.M., et al. "No evidence of rapid antiviral clearance or
clinical benet with the combination of hydroxychloroquine
and azithromycin in patients with severe COVID-19 infection."
Médecine et Maladies Infectieuses, vol. 50, no. 4, 2020, p. 384.
20. Laing, Roz, et al. "Ivermectin – Old Drug, New Tricks?" Trends
in Parasitology, vol. 33, no. 6, 2017, pp. 463-472. [CrossRef]
21. Caly, Leon, et al. "The FDA-approved drug ivermectin inhibits
the replication of SARS-CoV-2 in vitro." Antiviral Research, vol.
178, 2020, p. 104787. [CrossRef]
22. ŞİMŞEK YAVUZ, Serap, and Serhat ÜNAL. "Antiviral treatment
of COVID-19." Turkish Journal of Medical Sciences, vol. 50, no.
SI-1, 2020, pp. 611-619. [CrossRef]
23. Rajter, Juliana C., et al. "ICON (Ivermectin in COvid Nineteen)
study: Use of Ivermectin is Associated with Lower Mortality in
Hospitalized Patients with COVID19." 2020. [CrossRef]
24. Momekov, Georgi, and DenitsaMomekova. "Ivermectin as
a potential COVID-19 treatment from the pharmacokinetic
point of view: antiviral levels are not likely attainable with
known dosing regimens." 2020. [CrossRef ]

70 Chowdhury et al., A Comparative Study on Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin Therapy on COVID19 Patients. / doi: 10.14744/ejmo.2021.16263
25. Schmith, Virginia D., et al. "The Approved Dose of Ivermectin
Alone is not the Ideal Dose for the Treatment of COVID-19."
2020. [CrossRef]
26. Holmes, Natasha E., and Patrick G. Charles. "Safety and Eca-
cy Review of Doxycycline." Clinical Medicine Insights: Thera-
peutics 2009;1:471-482. [CrossRef]
27. Abegunde, Ayokunle T., et al. "Doxycycline plus ivermectin
versus ivermectin alone for treatment of patients with oncho-
cerciasis." Cochrane Database of Systematic Reviews, no. 1,
2016, p. CD011146. [CrossRef]
28. Sodhi, Mohit, and MahyarEtminan. "Therapeutic Potential for
Tetracyclines in the Treatment of COVID‐19." Pharmacothera-
py: The Journal of Human Pharmacology and Drug Therapy
2020;40:5:487-488. [CrossRef]
29. Conforti, Claudio, et al. "Doxycycline, a widely used antibiot-
ic in dermatology with a possible anti‐inammatory action
against IL‐6 in COVID‐19 outbreak." Dermatologic Therapy,
2020, p. e13437 [CrossRef]
30. Gautret P, Lagier J‐C, Parola P, Hoang VT, Meddeb L, Sevestre
J. Clinical and microbiological eect of a combination of Hy-
droxychloroquine and Azithromycin in 80 COVID‐19 patients
with at least a six‐day follow up: an observational study. Medi-
terr‐Infect.2020:101663 https://www.mediterranee-infection.
com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf
31. A Case Series of 100 COVID-19 Positive Patients Treated with
Combination of Ivermectin and Doxycycline Mtalam, R Mur-
shed, E Bhiuyan, S Saber, RfAlam, Rc Robin; Bangladesh Coll
Phys Surg 2020; 38: 10-15) DOI: https://doi.org/10.3329/jbcps.
v38i0.47512. [CrossRef]