Official Title

Use of Ivermectin as a Prophylactic Option in Asymptomatic Family

Close Contacts with Patients of COVID-19

NCT number: 04422561

Document date : 31-5-2020

 4 ‫ نموذج‬ZU- IRB #:

CONFLICT OF INTEREST DISCLOSURE

STATMENT

IRB#: --------------------------------------------------------------------------------

Principal Investigator: ): Prof /Waheed Shouman

Title of Protocol: Use of Ivermectin as a prophylactic option in

asymptomatic family close contacts for patients with COVID-19

Each author must indicate below that either (a) no financial conflict of interest exists with any
commercial entity whose products are described, reviewed, evaluated or compared in the
research proposal, except for that disclosed under ―Acknowledgements‖ or (b) a potential
conflict of interest exists with one or more commercial entities whose products are described,
reviewed, evaluated or compared in the research proposal through the existence of one or
more of the following relationships: the author is a full or part-time employee of a company;
has an existing or optional equity interest in a company; owns or partly owns patents licensed
to a company; has an ongoing retainer relationship (consultant ship, speaker, etc.) with a
company for which he/she receives financial remuneration; or has received financial
compensation for this publication or for the work involved in this publication.

I agree with the preceding conditions and provide the appropriate signatures and
information below accordingly (please photocopy this form and attach additional sheets as need
be with appropriate information and signatures affixed):

PI Name:Prof Waheed Shouman

-----27-5-2020 -----------------Date: Signature: Conflict of Interest: NO

Co-investigator Name:-
Name Conflict Signature

Ramadan M Nafae

Mostafa Ragab

Ashraf Sileem

e-mail : [email protected] ‫لجنة مراجعة اخالقيات البحث العلمى‬

 Lamiaa Gaber

Dalia Anas

Saad Rabae Samra

Mohamed elshabrawy

Abdelmonem Awad Hegazy

Tarek H al_Mahrouky

Ahmad Said

Ahmad Abbas

e-mail : [email protected] ‫لجنة مراجعة اخالقيات البحث العلمى‬

Title: Use of Ivermectin as a prophylactic option in asymptomatic family
close contacts for patients with COVID-19.

Researcher: Waheed M Shouman

Professor of Chest Medicine

Zagazig University

Egypt

Zip: 44519

Email: [email protected]

Tel. +201114812048

Introduction:

The 1st cases of COVID-19 were reported by the Chinese officials to the
WHO by 31 December 2019. Worldwide, the total cases by 23 April
2020 are 2 ,544 ,792 confirmed cases and 175 694 deaths [1]. No
consensus on a certain drug therapy for COVID-19 infection. A lot of
drugs are under trial or empirically included in treatment protocols for
COVID-19. Drug re-purposing is the most widely used method for rapid
response in the face of this epidemic. Trials to invent denovo medicines
may not be the perfect rationale, while the death and infection toll is on
the rise hourly.

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 One of these previously FDA approved drugs is Ivermectin.
Ivermectin is FDA-approved drug for Onchocerca volvulus and
Lymphatic Filariasis [2]. It is known to have wide-spectrum antiviral
activity against number of viruses under in vitro condition. [3-6]
Ivermectin has been shown to inhibit the nuclear import of host and viral
proteins. It has been demonstrated to limit infection by some RNA
viruses including influenza, dengue and West Nile viruses. Ivermectin
has similarly been shown to be effective against the DNA virus
pseudorabies virus (PRV) both in vitro and in vivo. In an in vitro study,
ivermectin was found to be an inhibitor of the SARS-CoV-2, with a
single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-
2 able to effect ~5000-fold reduction in viral RNA at 48 h. [7,8]

Rationale

Previous studies demonstrated the antiviral role of Ivermectin and

preliminary results from recent experimental reports highlighted an in
vitro capability of withholding SARS-CoV-2 replication

Research question

Is oral Ivermectin can prevent symptomatic COVI-19 infection in family

close contacts with patients diagnosed as having the disease by RT-PCR

Hypothesis

Ivermectin has an antiviral effect and may be effective in preventing

development of symptomatic infection in family close contacts with
patients having COVID-19

Aim

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 To study oral Ivermectin as a prophylactic treatment in family
close contacts with COVID-19 patients in the form of
development of symptoms

Objectives

To study the effect of oral Ivermectin as a prophylactic option in contacts

with COVID-19 patients

Individuals:

Adult family close contacts to COVID-19 positive patients diagnosed by

RT-PCR.

Materials and Methods:

Study Design interventional study

Sample Size: Family close contacts to 50 patients diagnosed as having

COVID-19 by RT-PCR

Location: Isolation facilities/Zagazig University Hospitals

Inclusion: Age more than 16 years, Asymptomatic household close

contacts

Exclusion: people previously treated for COVID-19, asymptomatic

contacts with who have HRCT chest done and suggestive for COVID-19
infection

Intervention :

All documented asymptomatic family contacts, starting on day of

diagnosis of their index case will receive Ivermectin according to body
weight as follows:

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 40-60 kg : 15 mg

60 -80 kg :18 mg

> 80 kg : 24 mg

This will be given as one dose at day one (diagnosis day), repeated once
at day 3

In literature, individuals can receive 600mcg per Kg of ivermectin daily

for 3 days without side effects (9,10)

Follow up:

1-These asymptomatic persons will be followed up for 2 weeks after the

diagnosis of index case for:

Symptoms development,

Radiological evaluation if symptoms developed (HRCT chest)

Swabs for SARS-2 Virus if symptomatic

Recording possible side effects during treatment: eg sleepiness and

fatigue

References:

https://www.who.int/docs/default-source/coronaviruse/situation-
reports/20200423-sitrep-94-covid-19.pdf?sfvrsn=b8304bf0_4.
Accessed 23-4-2020.

Aránzazu González Canga, Ana M. Sahagún Prieto, M. José Diez

Liébana, Nélida Fernández Martínez, Matilde Sierra Vega, Juan J.
García Vieitez. The Pharmacokinetics and Interactions of Ivermectin
in Humans—A Mini-review. AAPS J. 2008 Mar; 10(1): 42–46

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 Mastrangelo E, Pezzullo M, De Burghgraeve T, et al.
Ivermectin is a potent inhibitor of flavivirus replication
specifically targeting NS3 helicase activity: new prospects for an old
drug. J Antimicrob Chemother. 2012; 67(8):1884-1894.

Götz, V., Magar, L., Dornfeld, D. et al. Influenza A viruses escape from
MxA restriction at the expense of efficient nuclear vRNP import. Sci
Rep 6, 23138 (2016).

Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff

KM, Jans DA,Kehn-Hall K. Nuclear import and export inhibitors
alter capsid protein distribution in mammalian cells and reduce
Venezuelan Equine Encephalitis Virus replication, Antiviral Research
2013; 100(3): 662-672.

Azeem S, Ashraf M, Rasheed MA, Anjum AA, Hameed R. Evaluation of

cytotoxicity and antiviral activity of ivermectin against Newcastle
disease virus. Pak J Pharm Sci. 2015; 28(2):597-602.

Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA
approved drug ivermectin inhibits the replication of SARS-CoV-2 in
vitro. Antiviral Research 2020.

Ketkar H, Yang L, Wormser GP, Wang P. Lack of efficacy of ivermectin

for prevention of a lethal Zika virus infection in a murine system.
Diagnostic Microbiology and Infectious Disease 2019; 95(1): 38-40.

Smit MR, Ochomo EO,Waterhouse D et al Pharmacokinetics-

pharmacodynamics of high-dose ivermectin with dihydroartemisinin-
piperaquine on mosquitocidal activity and QT-prolongation
(IVERMAL). Clin Pharmacol Ther 2019; 105: 388–401

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 Navarro M, Camprubí D, Requena-Méndez A, et al. Safety of
high-dose ivermectin: a systematic review and meta-
analysis. J Antimicrob Chemother 2020;75:827-34.

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 Consort Flow diagram of Ivermectin prophylaxis trial

Assessed for eligibility (n= 379 contacts

of 93 confirmed index cases)

Enrollment

Excluded (n= 39 contacts and 10

confirmed index cases)
♦ Not meeting inclusion criteria (n=39 )
♦ Declined to participate (n= 0 )
♦ Other reasons (n= 0 )

Randomized (n= 340 contacts of 83 confirmed index cases)

Allocation
Allocated to intervention Ivermectin arm Allocated to intervention No intervention arm
(n= 228 of 57 confirmed index cases) (n= 112 of 26 confirmed index cases)
♦ Received allocated intervention (n= 228 ) ♦ Received allocated intervention (n= 112 )
♦ Did not receive allocated intervention (give ♦ Did not receive allocated intervention (give
reasons) (n= 0 ) reasons) (n= 0 )

Follow-Up
Lost to follow-up (n= 25 contacts of 5 Lost to follow-up (n= 11 contacts of 2
confirmed index cases) confirmed index cases)

Discontinued intervention (failure to follow up Discontinued intervention (failure to follow up

contacts for 14 days) (n= 25) contacts for 14 days) (n=11)

Analysis
Analysed (n=203 contacts of 52 confirmed index Analysed (n=101 contacts of 24 confirmed
cases) index cases)
♦ Excluded from analysis (give reasons) (n= 0)
♦ Excluded from analysis (give reasons) (n=0)
Statistical analysis

All data were collected, tabulated and statistically analyzed using SPSS 22.0
for windows (IBM Inc., Chicago, IL, USA) and MedCalc 13 for windows
(MedCalc Software Bvba, Ostend, Belgium). Continuous Quantitative
variables were expressed as the mean ± SD & median (range), and
categorical qualitative variables were expressed as absolute frequencies
(number) & relative frequencies (percentage). Continuous data were
checked for normality by using Shapiro Walk test. Mann-Whitney U test
was used to compare between two groups of non-normally distributed data.
Categorical data were compared using Chi-square test or Fisher's exact test
when appropriate. Relative risk and its 95%Confidence interval (CI) was
calculated to estimate risk of COVID-19 infection in addition forest plot was
plotted. Univariate and multivariate binary logistic regression were built to
find predictors for COVID-19 protection. All tests were two sided. p-value <
0.05 was considered statistically significant.
Results

As regard index cases, there were 9 (11.8%) mild , 44 (57.9%) moderate and
23 (30.3%) severe cases. In the ivermectin group, there were 8 (53.3%) mild
, 6 (40%) moderate and 1 (6.7%) severe cases. While in the no-intervention
group, there were 31 (52.5) mild, 21 (35.6%) moderate and 7 (11.9%) cases.

Figure (1): Scatter plot shows relationship between contact time in days and
number of contacts that developed COVID-19; dashed line represent best
fitted line (quadratic model).
There was insignificant linear correlation between contact time in days and
number of contact that developed COVID-19. The appropriate forecasting
for number of contact that developed COVID-19 based upon contact time in
days was quadratic model.

Figure (2): Box plot shows relationship between isolation and number of
contacts that developed COVID-19.

There was insignificant difference between index cases isolated at hospital

and index cases isolated at home regarding number of contact that developed
COVID-19 where mean number of contact that developed COVID-19 (±SD)
was 2.14 (±1.35) versus 2.07 (± 2.26) respectively (p-value=0.208)
Table (1): Comparison between Ivermectin arm and non-intervention
arm regarding basic characteristics.

Ivermectin arm Non-intervention arm

p-
(N=203) (N=101) Test
value
Basic characteristics No. % No. %

Gender

Male 106 52.2% 50 49.5% 0.199a 0.656

Female 97 47.8% 51 50.5%

Age (years)

Mean ± SD 39.75 ± 14.93 37.69 ± 16.95 - 0.175

1.357
Median (Range) 38 (16 – 94) 35 (16 – 78)
b

Any comorbidity

Absent 156 76.8% 75 74.3% 0.248a 0.619

Present 47 23.2% 26 25.7%

a: Chi-square test; b: Mann Whitney U test; p< 0.05 is significant.

Table (1) shows that there was no significant difference between both arms
as regard gender, age or comorbidities. The median (range) age for both
groups was 38 (16-94) and 35 (16-78) years respectively.

The most common comorbidities were; hypertension in 16 (7.9%) and 13

(12.9%), DM in 13 (6.4%) and 10 (9.9%), bronchial asthma in 7 (3.4%) and
2 (2%), ischemic heart disease in 6 (3%) and 1 (1%), hypothyroidism in 5
(2.5%) and 1 (1%), chronic kidney disease in 2 (1%) and 1 (1%), liver
cirrhosis in 1 (0.5%) and 1 (1%), cardiomyopathy in 2 (1%) and 0% in both
ivermectin and no-intervention group respectively.

Table (2): Comparison between Ivermectin arm and non-intervention

arm regarding outcome.

Ivermectin arm Non-intervention arm

(N=203) (N=101) Test p-value

Outcome No. % No. %

Symptoms

Absent 188 92.6% 42 41.6% 95.351 <0.001

a
Present 15 7.4% 59 58.4%

Days until symptoms

Mean ± SD 3 ± 1.30 4.13 ± 1.78 - 0.017

2.391b
Median (Range) 2 (2 – 6) 4 (2 – 10)

2 days 8 53.3% 12 20.3% 10.150 0.118

a
3 days 2 13.3% 13 22%

4 days 3 20% 11 18.6%

5 days 1 6.7% 13 22%

6 days 1 6.7% 1 1.7%

7 days 0 0% 8 13.6%

10 days 0 0% 1 1.7%
CT suspect

Negative 7 50% 30 51.7% 0.013a >0.05

Positive 7 50% 28 47.3%

CBC suspect

Negative 2 14.3% 5 8.6% 0.412 a >0.05

Positive 12 85.7% 53 91.4%

Protection rate

No protection 15 7.4% 59 58.4% 95.351 <0.001

a
Protection 188 92.6% 42 41.6%

a: Chi-square test; b: Mann Whitney U test; p< 0.05 is significant.

Table (2) shows that 15 contacts (7.4%) developed COVID-19 in the

ivermectin arm compared to 59 (58.4%) in the no-intervention arm, all of
them were symptomatic, according to the study protocol . The difference
was highly significant (p<0.001). The median (range) days for developing
the disease was 2 (2-6) in ivermectin group compared and 4 (2-10) in the no-
intervention group, the difference was significant (p<0.017). Ten contacts
(66.6%) developed symptoms in 1st 3 days in ivermectin group, and none
developed it after 6 days. In the no-intervention arm, 25 (42.3%) developed
symptoms in the 1st 3 days and continued to the 10 days.

HRCT of the chest was performed in 14 out 15 contacts and in 58 of the 59

contacts who developed symptoms in ivermectin and no-intervention
groups, respectively. The missed one case in each arm had symptoms and
positive RT-PCR without other investigations. Chest HRCT was positive for
COVID-19 in 7 (50%) and 28 (48.3%) in ivermectin and no-intervention
groups, respectively.

Complete blood count was performed also in 14 and 58 contacts who

developed symptoms in ivermectin and no-intervention groups respectively.
Positive criteria in CBC was present in 12 (85.7%) and 53 (91.4%) in
ivermectin and no-intervention groups respectively.

Table (3): Comparison between Ivermectin arm and non-intervention

arm regarding protection rate stratified by basic characteristics.

Protection rate

Ivermectin Non-intervention Testa p-value

arm
arm

All patients 92.6% 41.6% ------ ------

Index case Mild 92.9% 35% 11.381 0.001

severity
Moderate 95.6% 55.8% 42.666 <0.001

Severe 85.2% 28.9% 29.928 <0.001

Age ≤60 93.8% 41.3% 91.514 <0.001

>60 84% 44.4% 5.320 0.034

Gender Male 94.3% 42% 53.482 <0.001

Female 90.7% 41.2% 42.278 <0.001

Any No 95.5% 45.3% 77.474 <0.001

comorbidity
Yes 83% 30.8% 19.899 <0.001
 DM No 94.7% 42.9% 96.308 <0.001

Yes 61.5% 30% 2.253 0.214

HTN No 93% 44.3% 81.372 <0.001

Yes 87.5% 23.1% 12.272 <0.001

a: Chi-square test; p< 0.05 is significant.

Table (3) shows that 7.4% contacts developed diseases in ivermectin group
while they were 58.4% in no-intervention group. Contacts tend to be
infected when the index case was severe; 14.8% and 71.1% in both groups,
respectively. The protection rate for ivermectin was more prominent in
contacts less than 60 years old (6.2% infected compared to 58.7% if no
intervention) , but still effective in elder than 60 years (16% infected
compared to 55.6% if no intervention).

Table (4): Predictors for COVID-19 protection.

Univariate Model Multivariate Model

OR (95%CI) p-value OR (95%CI) p-value

Arm

Ivermectin 12.533 (7.408-21.205) <0.001 11.445 (4.444-29.475) <0.001

Non-intervention Reference

Index case severity <0.001 0.018

Mild 1.429 (0.722-2.828) 0.306 1.257 (0.486-3.247) 0.637

Moderate 6.120 (4.010-9.341) <0.001 2.816 (1.355-5.851) 0.006

 Severe Reference

Age

Age≤60 years 3.154 (2.386-4.169) <0.001 0.254 (0.101-0.639) 0.004

Age>60 years Reference

Gender

Male 3.457 (2.373-5.036) <0.001 0.836 (0.437-1.600) 0.588

Female Reference

Any comorbidity

Absent 3.812 (2.774-5.239) <0.001 2.222 (0.967-5.108) 0.060

Present Reference

OR: Odds Ratio; 95%CI: 95%Confidence Interval.

Table (5) shows that ivermectin have very highly significant role in the
protection of SARS-CoV-2 infection. . It has an OR of 12.533 and 11.445
when compared to no intervention in both univariate and multivariate
models, respectively. Ivermectin protection was not affected by gender or
comorbidities in multivariate model.

As regard ivermectin side effects, they were reported in 11 (5.4%) contacts.

These were; diarrhea (1.5%), nausea (1%), fatigue (1%), sleepiness (0.5%),
abdominal pain (0.5%), heart burn (0.5%), tingling and numbness (0.5%)
and lastly burning sensation (0.5%)