Ivermectin as a Chemoprophylaxis for Close Family Contacts

Ivermectin as a Chemoprophylaxis for Close Family Contacts of RT-PCR Confirmed COVID-19 Patients Waheed Shouman Prof. of Chest Medicine Zagazig University Egypt

v Waheed M Shouman v Abdelmonem Awad Hegazy v Ramadan M Nafae v Moustafa I Ragab v Saad R Samra v Ahmed M Said. v Mohamed El shabrawy Mahmoudy v Dalia Anas Ibrahim v Lamiaa Gaber Zake v Ahmad Abbas v Tarek H Al-Mahrouky v Ashraf E Sileem

Introduction

COVID-19 Cases and Deaths According to WHO Month Total Cases Total deaths % of Deaths May 2020 2, 844, 491 149, 397 5. 252% June 2020 4, 250438 136, 696 3. 216% July 2020 6, 920, 633 165, 048 2. 385% August 2020 7, 748, 133 170, 014 2. 194% Septemper, 27 th 2020 7, 876, 805 152, 300 1. 934% October , 28 th 10, 610, 506 166, 285 1. 567% 1 -30 Nonember 15, 897836 256, 079 1. 611%

v No consensus on a certain drug therapy for COVID-19 infection has been documented up till now. v Currently, many drugs are under clinical trials or empirically included in treatment protocols for COVID-19. v Drug repurposing is the most widely used method for rapid response in the face of this pandemic

v Trials to invent denovo medicines might not be the perfect rationale, while the infection and death numbers are rising daily. v Effective vaccine may lag behind the urgent need. Despite the current pandemic continues all around the world, there is not yet a proven effective vaccine; and there is not yet a proven chemoprophylactic strategy. v This emerges the need to protect persons in close contact with the patients

v One of such drug trials was through use of ivermectin, the previously FDA-approved drug. v ivermectin has been previously approved for management of Onchocerca volvulus and lymphatic filariasis v Currently, it is under scrutiny for its role in management of COVID-19 in different clinical trials worldwide. v To date, there are more than 36 trials registered at clinicaltrials. gov investigating its role

v It is known to have a wide-spectrum antiviral activity against a number of viruses under in vitro investigations. v Ivermectin has been shown to inhibit the nuclear import of viral proteins. v Moreover, it has been demonstrated to limit infection caused by some RNA viruses including influenza, dengue and West Nile viruses

v In an in vitro study, ivermectin was found to be an inhibitor of the SARS-Co. V-2, with a single addition to Vero-h. SLAM cells 2 h post infection with SARS-Co. V-2 able to effect ~5000 -fold reduction in viral RNA at 48 h

v The rate of secondary attack of SARS-C 0 V-2 is high among family members in close contact especially the household (about 10 -15%). v Social distancing, isolation, and infection control measures are of paramount importance, but might be insufficient.

v The aim of this study was to evaluate possible role of oral ivermectin as a post-exposure chemoprophylactic drug in asymptomatic family members in close contact with RTPCR confirmed COVID-19 patients

Participants and Methods

Study Registration and Approval q This was a prospective community-based, interventional randomized open label-controlled study; registered at clinicaltrials. gov; NCT 04422561 q The study has been approved by the IRB of Zagazig Faculty of Medicine under the code: 6150 -31 -5 -2020 q It was carried out at Faculty of Medicine, Zagazig University, Egypt; during the period from June 1 to July 28

Participants q Asymptomatic household family in close contact with cases of COVID-19 diagnosed and confirmed by RT-PCR at Zagazig University Hospitals (ZUH), different triage and isolation hospital q It was planned to include contacts of 50 RT-PCR confirmed COVID-19 patients in each arm. But during recruitment, and as the trial was non-blinded, the high protective efficacy detected for ivermectin made the researchers to stop prematurely the non-intervention arm

q Inclusion criteria included asymptomatic household close contacts to confirmed RT-PCR COVID-19 index case, with age equal to or more than 16 years q Exclusion criteria were any contact developed symptoms or diagnosed as COVID-19 before enrollment, failure to follow-up contacts for 14 days, and failure to document the index case when there was more than one case in a family

Two arms (or groups) were designed according to use of ivermectin Group one (ivermectin group) contacts received ivermectin on day of the diagnosis of their index case. It was given as one dose on empty stomach at day one (diagnosis day), repeated once more at day 3 (total 2 doses). The dose was adjusted according to body weight (BW) as follows: 15 mg/day for subjects of 40 -60 kg BW; 18 mg/day for 60 -80 kg; and 24 mg/day for those > 80 kg BW. Second group (non-intervention group), none received ivermectin i. e. there was no contacts of same index case received the drug and others no (all or none rule)

Follow up Both groups were followed-up for two weeks, for development of symptoms suggestive of COVID-19 including fever with respiratory symptoms plus or minus others e. g. anosmia or GIT symptoms [12]. Follow-up sheet was administered for both the managing physician and contacts

q If any contact developed symptoms suggestive of COVID 19, complete blood count (CBC) and C-reactive protein (CRP) were done just after onset of symptoms; plus, a high -resolution CT (HRCT) of the chest within 3 -5 days was performed. q In one case in ivermectin group and one case in nointervention group, CBC and HRCT of the chest were not done, as only reverse transcription polymerase chain reaction (RT-PCR) test was performed.

q Due to limitation of performing RT-PCR for suspect COVID 19 patients, only 4 subjects in ivermectin group and 12 subjects in the no-intervention group performed it and were positive for SARS-Co. V-2. q According to the Egyptian Ministry of Health and Population (MOHP) guidelines (version 1. 4, May 30 2020), patients are considered a COVID-19 case with suggestive clinical history with positive contact history, and/or laboratory results (lymphopenia and or leucopenia) and/or suspicious HRCT findings

q Cases were categorized, as regard severity, as follow: mild (symptoms and laboratory only), moderate (as mild with signs of pneumonia in CT chest), and severe or critical q In the ivermectin group, participants were followed-up for possibility of drug side effects. Our primary outcome was prevention of COVID-19 in any of contacts by day 14 of follow-up

Results

Ivermectin arm(N=203) Non-intervention arm(N=101) Basic characteristics Gender No. % Male 106 52. 2% 50 49. 5% Female 97 47. 8% 51 50. 5% Test pvalue 0. 199 a 0. 656 1. 357 b 0. 175 0. 248 a 0. 619 Age (years) Mean ± SD Median (Range) 39. 75 ± 14. 93 37. 69 ± 16. 95 38 (16 – 94) 35 (16 – 78) Any comorbidity Absent 156 76. 8% 75 74. 3% Present 47 23. 2% 26 25. 7% Comparison between Ivermectin arm and nonintervention arm regarding basic charactertics.

Percentages of contacts with severity of index cases 70 66, 5 60 50 42, 6 37, 6 40 30 26, 6 19, 8 20 10 6, 9 0 Mild Ivermectin group Moderate Severe Non-ivermectin group Columns showing percentages of severity of the disease in index cases in the two groups

Percentages of contacts developing disease 70 58, 4 60 53, 3 52, 5 50 40 40 35, 6 30 20 11, 9 10 7, 4 6, 7 0 Total percentage Mild Ivermectin Non-ivermectin 2 Moderate Severe Columns showing percentages of contacts who developed COVID-19; the total in the two groups and percentages of severity of disease.

Comparison between Ivermectin arm and non-intervention arm regarding outcome.

Ivermectin side effects: They were reported in 11 (5. 4%) contacts. q Diarrhea (1. 5%), q Nausea (1%), q Fatigue (1%), q Sleepiness (0. 5%), q Abdominal pain (0. 5%), q Heart burn (0. 5%), q Tingling and numbness (0. 5%) q Burning sensation (0. 5%)

Limitations of the current work: q q The small number of the non-intervention group The low rate of RT-PCR done in contacts with symptoms The used dose of ivermectin is empirical There was exclusion of contacts other than the asymptomatic close family contacts. q Exclusion of children q Absent study of home conditions, crowdness, and smoking,

Conclusion Ivermectin is suggested to be a promising effective chemoprophylactic drug against COVI-19. Ivermectin is an inexpensive, available and quite safe drug

Recommendations: q As this is the first report regarding use of ivermectin in COVID-19 prophylaxis, it is very appropriate to promptly and rigorously study this drug further. q Future studies are recommended using different doses and larger numbers of cases. q We also recommend ivermectin to be studied in pre- and post-exposure chemoprophylaxis in other situations e. g. for healthcare workers

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