Singapore researchers, led by the National University of Singapore, reported on a large clinical trial conducted last Spring involving over 3,000 migrant workers residing in Tuas South dormitory. Published in the International Journal of Infectious Disease (IJID), the study showcased the positive impact of oral hydroxychloroquine and povidone-iodine spray for COVID-19 prophylaxis via an open-label randomized clinical trial. The researchers report that the “chemoprophylaxis agents were well tolerated” and that infections rates failed to differ with oral ivermectin and zinc/vitamin C. Overall, they report that the combination of oral hydroxychloroquine and povidone-iodine spray reduced the spread of COVID-19 in high transmission settings. The use of hydroxychloroquine targeting COVID-19, now controversial in much of the West, is still heavily in use in many parts of the world targeting COVID-19. In this study, the sponsors deviated from other protocols for ivermectin prophylaxis opting for just one dose.
This clinical trial (NCT04446104) sought to investigate the use of generic, repurposed drugs in a closed dormitory environment housing migrant workers in Singapore. The study team, led by Singapore National University Hospital, sought out and found a real-life scenario where prophylaxis treatment could reduce the impact of the disease.
The Phase 3 clinical trial included five (5) arms, including 1) Hydroxychloroquine (participants take 400mg doses followed by 200mg daily dose for 42 days); 2) Ivermectin (participants receive single 12mg tablet); 3) Zinc/Vitamin C (participants received zinc table 80mg/vitamin C 500mg daily for 42 days); 4) Povidone-iodine throat spray (3 times daily) for 42 days; and 5) Active Comparator (Participants receive vitamin C tablet 500mg daily for 42 days).
The authors reported that the primary outcome sought was to measure laboratory evidence of SARS-CoV-2 infection as demonstrated by either (1) a positive serologic test for SARS-CoV-2 antibody on day 42 or (2) positive PCR test for SARS-CoV-2 at any time between baseline and day 42.
Out of a total of 3,047 asymptomatic participants (mean age, 33 years and all men) who at the time of the study commencement were deemed seronegative to COVID-19 were included in the primary analysis.
Out of 1,681 of the 3,037 (55.4%) participants diagnosed with SARS-CoV-2, those taking hydroxychloroquine did best (212 out of 432 or 49%) while the povidone-iodine throat spray group also benefits (338 out of 735 or 46%). In the Vitamin C group, 433 out of 619 or 70% became positively diagnosed.
The study team reported that based on an alpha of 0.0125 (account for multiple comparisons), no statistically significant differences were observed between zin/vitamin C (300 out of 634 or 47%) and ivermectin one dose (398 out of 617 or 64%, compared with vitamin C.
The study team found that compared with vitamin C, a significant absolute risk reduction (98.75% confidence interval) were observed for oral hydroxychloroquine (21%, 2-42%) and povidone-iodine throat spray (24%,7-39%). No statistically significant differences were observed with oral zinc/vitamin C combination (23%,-5 to+41%) and ivermectin (5%,-10 to+22%). The study team, led by corresponding author Raymond Chee Seong Seet, MBBS, FRCP, Department of Medicine, Yoo Loo Lin School of Medicine, National University of Singapore found side effect-based interruptions highest among those who received the zinc/vitamin C combination (6.9%), followed by vitamin C (4.7%), povidone-iodine (2.0%) and hydroxychloroquine (0.7%).
Interestingly, for the ivermectin arm, the protocol only appeared to include one dose, which doesn’t follow any other existing protocols established for that regimen. The study team concluded that chemoprophylaxis with either oral hydroxychloroquine or povidone-iodine throat spray was superior to oral vitamin C in reducing SARS-COV-2 infection in young healthy men.
Associate Professor Raymond Seet, Senior Consultant, Division of Neurology, Department of Medicine, NUH and Department of Medicine, NUS Yong Loo Lin School of Medicine, emailed TrialSite to clarify the rationale for the study’s ivermectin dosage:
“Treatment trials have used higher doses than what we did for this prevention trial. Some have tried doses 5 times higher while others have suggested that an even higher dose may be needed for COVID treatment. We were uncertain whether higher doses were necessary for COVID prevention as there was insufficient safety information for mass drug administration of ivermectin at these doses. We chose a single dose of ivermectin of 12mg as this worked out to approximately 200ug/kg which is the dose licensed for scabies treatment. This ensured that all agents were used at or below their currently licensed doses for common conditions in Singapore to avoid the concerns about toxicity which were heightened at the time due to the paper from Mehra et al in the Lancet which was subsequently retracted.”
The sponsors set up an open-label, parallel randomized controlled trial evaluating the various regimens identified above. They randomized subjects in clusters with each one defined by the residential floor of a multi storey dormitory complex. The protocol called for a single intervention per floor, which aligned recruitment workflow with strict floor level movement rules and associated medication instructions to prospective participants. The goal here was to minimize the possibility of errors given the scale and timeliness of recruitment.
Note that this differs from individual randomization, which would have made necessary five different medications allocated in parallel. In this situation, that could have led to medication dispensing errors as well as exchanges within resident rooms and floors. While the study team opted out of convenience to make this study open-labeled for ease of managing the study given the different routes of administration, that is oral versus throat spray for example, as well as medication scheduling (single dosing, once daily and twice daily).
This trial was approved by the Domaine-Specific Review Board, National Healthcare Group, the Ministry of Health, the multi-ministerial Joint Task Force and the overall study was conducted under a Clinical Trial Authorization by the Health Sciences Authority, which oversees all clinical trials in Singapore.
Ivermectin for Prophylaxis: A Deviation from Other Studies
Of interest, the Singapore study seems to deviate from other ivermectin prophylaxis studies. For example, here the sponsors took an ultra-conservative approach, noting that pharmacokinetic studies suggested a higher dose of ivermectin well over approved limits and cited “sparse human data are available to support safety and efficacy of ivermectin against SARS-CoV-2 at these doses.” Hence, they opted to keep the dosage of ivermectin to within the approved limits of 200ug/kg and a single dose of 12 mg was administered in participants who weighed >60kg.
But in the Benhan Study, which commenced just a month after the Singapore study, the prophylaxis group received a 4-days course of Ivermectin 400 mcg/kg body weight maximum 4 tablets (6mg / tablet) once daily dose before breakfast plus standard care as issued by Egyptian protocol.
Even with hydroxychloroquine, the minimum days for prophlaxis is typically five (5) days, and the Singapore group used it for over 40 days.
In the COVID-19 real time running analysis, among therapeutic benefits, prophylaxis use shows 85% improvement (RR 0.15 [0.09-0.25].
Raymond Chee Seong Seet, MBBS, FRCP, Department of Medicine, Yoo Loo Lin School of Medicine, National University of Singapore (corresponding author)
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