|Year : 2021 | Volume
| Issue : 2 | Page : 109-114
Efficacy of Single-Dose Ivermectin on Virologic and Clinical Recovery in COVID-19: A Randomized Controlled Trial
Romit Saxena1, Muthu Rajanagam1, Urmila Jhamb1, Vikas Manchanda2, Sonal Saxena2, Pallavi1
1 Department of Pediatrics, Maulana Azad Medical College and Associated LNJP Hospital, New Delhi, India
2 Department of Microbiology, Maulana Azad Medical College and Associated LNJP Hospital, New Delhi, India
|Date of Submission||14-Jul-2021|
|Date of Acceptance||05-Aug-2021|
|Date of Web Publication||27-Aug-2021|
Dr. Romit Saxena
Department of Pediatrics, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi 110002
Source of Support: None, Conflict of Interest: None
Background: Coronavirus disease 2019 (COVID-19) pandemic mounts an ever increasing challenge on healthcare resources. Ivermectin shows promise in in vitro studies on coronavirus, but there are few prospective trials on currently approved dosage recommendation for the treatment of COVID-19. Aims: To study the virologic and clinical recovery after single-dose ivermectin, given within first 5 days of symptom onset. Settings and design: Prospective, open-labeled, randomized controlled trial. Patients were recruited in between August 30, 2020, and November 6, 2020, at a single referral center for patients with COVID. Materials and methods: The study participants included patients presenting with severe acute respiratory syndrome coronavirus 2 infection. The patients were randomized to receive a single-dose ivermectin, 0.2 mg/kg in the treatment group (TG). Both groups [TG and control group (CG)], continued to receive standard treatment. Results: The recruited cohort was comparable in the two arms of the study, except age and height. There was no statistically significant difference in virologic clearance between the two arms (percentage COVID positive day 7: TG: 34.2% vs. CG: 52.6%, P = 0.165). Conclusion: Our study shows that after administration of single dose of currently approved doses of ivermectin (0.2 mg/kg), there does not exist a significant virologic or clinical recovery in COVID-19 disease.
Keywords: Coronavirus disease, randomized controlled trial, RT-PCR
|How to cite this article:|
Saxena R, Rajanagam M, Jhamb U, Manchanda V, Saxena S, Pallavi. Efficacy of Single-Dose Ivermectin on Virologic and Clinical Recovery in COVID-19: A Randomized Controlled Trial. MAMC J Med Sci 2021;7:109-14
|How to cite this URL:|
Saxena R, Rajanagam M, Jhamb U, Manchanda V, Saxena S, Pallavi. Efficacy of Single-Dose Ivermectin on Virologic and Clinical Recovery in COVID-19: A Randomized Controlled Trial. MAMC J Med Sci [serial online] 2021 [cited 2021 Dec 3];7:109-14. Available from: https://www.mamcjms.in/text.asp?2021/7/2/109/324744
| Introduction|| |
Coronavirus disease 2019 (COVID-19) has placed an unprecedented challenge on public health, with unemployment, death, and social disruption. Although the vaccine has been developed recently, it will still take sometime, before a substantial percentage of population is vaccinated, given the logistics involved. Hence, there has been an emphasis on exploring affordable alternatives for COVID treatment. Many drugs have been used studied in the fight against COVID.,
Ivermectin is one such drug that has sparked international attention. Its wide-spectrum antiviral activity under in vitro conditions, including for COVID-19, excellent safety profile, with more than 35 years of experience in its use and over 2.7 billion doses having been distributed, make it a very attractive candidate in the fight against COVID-19.,,,,,, The currently approved dose recommendations are 150 to 200 µg/kg, and there are no major safety concerns at this dose., We embarked on a randomized controlled study to establish whether the currently approved dosages have any impact on virologic clearance and clinical improvement in patients with COVID-19.
| Subjects and Methods|| |
This is a single center, open-labeled, randomized controlled trial, aimed to assess the efficacy of single-dose ivermectin given within first 5 days of symptom onset. The microbiologic efficacy of the drug was assessed by reverse transcription polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), performed at 3rd and 7th day after recruitment.
Patients were enrolled if they were admitted within 5 days of symptoms and were confirmed positive for SARS-CoV-2, either by RT-PCR or rapid antigen test in a nasopharyngeal, oropharyngeal, or combined swab.,, Additional criterion for recruitment, included age 5 to 65 years (and weight more than 15 kg)., The drug was cleared by the internal hospital multidepartmental committee for use in patients with COVID in the dosage decided by existing literature., We excluded any patients, with known history of ivermectin allergy, intake of ivermectin in previous 15 days, refusal of consent or with certain comorbidities (as acute or chronic renal failure, coronary disease, malignancy, or cerebrovascular disease).
Our exclusive COVID hospital followed the hybrid model, due to the increased COVID case load, where other medical specialties as surgery and pediatrics, supported adult medicine care and admissions. Most patients were relatives of the symptomatic children who were admitted under our care, and stayed in the hospital for the duration of child’s treatment. This enabled us to monitor them closely clinically for symptom resolution and side effects, for at least a week.
After getting written informed consent from patients, the investigators randomized the patients into two groups, based on simple block randomization, with variable block sizes of 4, 6, and 8, using a computer-generated randomization sequence. The random number sequence was generated by a doctor, not participating in the study. Allocation concealment was carried out using sequentially numbered, opaque and sealed envelopes, opened just prior to recruitment of patients. The patients were then randomized into either treatment group (TG) or control group (CG).
The CG was offered standard treatment, which included symptomatic treatment, zinc, and vitamin C. The TG was offered all the modalities in standard treatment with additional ivermectin. Single dose of ivermectin was administered, at dose of 0.2 mg/kg.
The patients were then monitored at baseline and clinically, everyday by the investigators, for appearance of new symptoms or symptom resolution, till 7 days from drug administration/recruitment. They were also monitored for drug-related side effects. An RT-PCR swab was collected on days 3 and 7, and viral load (Ct value) was determined. Combined oronasopharyngeal swab collection, transportation, and processing were as per standard guidelines.,
The combined oronasopharyngeal swab samples were transported from the department to the laboratory as soon as possible while maintaining a strict cold chain. After reaching the laboratory, the samples were processed immediately or stored at ‒20°C until processing was completed.
The real-time RT-PCR assay used the TaqMan fluorogenic probe-based chemistry that used the 50 nuclease activity of Taq DNA polymerase and enabled the detection of a specific RT-PCR product as it is accumulated during RT-PCR cycles. Cycle conditions and RT-PCR reagent preparation were according to the Indian Council of Medical Research protocol., A specimen was identified as screen positive for the SARS-CoV-2 if the amplification curve for the CoV envelope (E) gene crossed the threshold line within 35 cycles. The viral load was assessed in terms of the cycle threshold (Ct) value of the E gene., The Ct value is the number of cycles of amplification required to generate a fluorescent signal.
Samples that were screened positive for E gene were further confirmed using RT-PCR with SARS-CoV-2-specific primers of viral RdRp gene (RNA-dependent RNA polymerase) and HKU ORF (open reading frame) sequence. A specimen was confirmed positive for novel coronavirus 2019 only if the curves crossed the threshold line within 35 cycles for E gene, and either/both RdRp or/and ORF gene.
After discharge, patients were followed up on day 21, through a telephonic interview, to assess for clinical symptoms and side effects of drugs. The clinical and laboratory data were recorded in a predesigned proforma, and entered into excel, in a password-protected computer. It was further analyzed using Microsoft excel 2013 and SPSS.
The primary objective of the study was to assess the efficacy of single-dose ivermectin, given within first 5 days of symptom onset on virologic clearance. It was assessed by RT-PCR for SARS-CoV-2, on 3rd and 7th day of treatment. Secondary objectives included assessment of symptom resolution, drug safety profile or appearance of new symptoms by daily clinical assessment, in the hospital for the first week. It was further assessed at 21 days from recruitment, by telephonic interview.
Assuming a 100% positivity rate at days 7 and 8 of untreated disease and considering a drop in prevalence by 30% after drug administration as target expected, with power of 90%, a sample size of 56 was calculated (28 in each group). Further after assuming 10% attrition rate, sample size of 62 was calculated. However, later it was decided to continue to recruit, till the 21st day follow-up of 62nd patient, keeping a possibility of dropouts. Therefore, 84 patients were finally recruited.
The data are presented as number and percentage, mean and standard deviation, or median and interquartile range. For comparison of categorical versus categorical data, Chi-squared test was used. For comparison of categorical versus quantitative data, for unrelated samples, Student t test or Mann–Whitney U test was used. For related samples, paired t test or Wilcoxon sign-rank test was used.
The trial was approved by the institutional ethics committee (vide F.1/IEC/MAMC/ (77/05/2020/No 192), and was registered with Clinical Trials Registry − India (vide no. CTRI/2020/08/027394). Before allocation into the two study arms, informed consent/assent was taken from all participants.
| Results|| |
Patients were recruited between August and November 2020, and were further followed up for 21 days, including the first week under hospital stay, after recruitment. About 415 patients got admitted during this time period. [Figure 1] shows the flow chart of the study.
The treatment and CGs were comparable at baseline, except in terms of age and height. (TG had younger population) [Table 1].
|Table 1 Baseline clinico-epidemiologic comparison between treatment and control groups|
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All patients remained stable across the two groups and were discharged. At day 3 after recruitment, there was no difference between COVID positivity rate (TG: 26/38 vs. CG: 27/38, P = 1). After 7 days though there were more patients, who had become COVID negative, by RT-PCR in the ivermectin subgroup when compared with the CG, but the difference was not statistically significant (COVID+ status: TG: 13/38 vs. CG: 20/38, P = 0.165). There was also improvement observed in Ct values, but there was no statistical significance between the two groups [Table 2].
|Table 2 Baseline comparison in laboratory parameters between treatment and control groups|
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At baseline, more patients were symptomatic in the TG, than the controls, with most being in the mild category. The common symptoms in the two groups included fever, cough, coryza, dyspnea, expectoration, fatigue, myalgia, sore throat, diarrhea, anosmia, ageusia, pain abdomen, headache, and febrile seizure. There was no worsening (escalation of severity category) over the course of stay in any patient. There was no significant difference in symptom resolution between the two subgroups [Table 3] and [Table 4].
|Table 3 Primary outcome: virologic recovery and cycle threshold values at days 3 and 7 of follow-up|
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Three weeks follow-up
Three patients had symptoms at the end of day 21 of follow-up. One patient in CG, who was asymptomatic at admission, had intermittent fatigue which persisted between days 10 and 21 from enrolment. One patient in TG was admitted again on day 17, had abdominal pain, with presumed acalculous cholecystitis, and discharged on conservative management. One adolescent male in TG had associated tubercular pleural effusion at the time of enrolment in the study and had intermittent fever spikes till day 18 after enrolment. No other patient had any persistent/new symptoms, side effects of ivermectin, or required hospitalization.
| Discussion|| |
In 2015, William Campbell and Satoshi Ōmura were awarded a joint Nobel Prize in Medicine for their discovery and development of ivermectin. This drug is a part of World Health Organization model list of essential medicines. It has been used with varying success in other RNA viruses as dengue, zika, and yellow fever. Interest developed in the potential use for ivermectin in COVID-19, after the study by Caly et al., which demonstrated an impressive reduction (>5000 fold) in SARS-CoV-2 viral RNA in samples treated with 5 µM ivermectin at 48 hours of single exposure. It has been proposed that ivermectin could inhibit the host importin protein (Imp α/β1 heterodimer), which acts as a transporter in nucleocytoplasmic shuttling of the SARS-CoV-2 nucleocapsid protein. Due to this hypothesis, it was proposed that its administration early in the course of disease could help attenuate severity and duration of infection.
Since then researchers have emphasized multiple drug combinations including ivermectin with varying success., We intended to simplify and study the impact of a singular drug on COVID-19 disease, when compared with standard treatment. In our randomized controlled trial, we did not observe any benefit on COVID-19 recovery on day 3 (TG: 68.4% vs. CG: 71.1%, P = 1) or at day 7 after start at treatment (TG: 34.2% vs. CG: 52.6%, P = 0.165). There was no significant difference on duration of symptoms in the two groups as well, or the overall outcome. However, our study further establishes the robust safety profile of the drug.
Our study validates the hypothesis of lack in therapeutic efficacy of standard dose ivermectin in COVID-19, based on the findings of the two-compartment population pharmacokinetic model for ivermectin. They had predicted that ivermectin is unlikely to reach the IC50 in lungs after oral administration of the approved dose or doses 10 times higher than the approved doses as a single dose.
Though retrospective studies on single-dose ivermectin have claimed mortality benefit and increased virologic clearance, the same could not be demonstrated in our prospective randomized controlled trial (RCT). Recent studies with longer courses of ivermectin (12 mg once daily for 5 days) have showed therapeutic benefit, when compared with placebo. Another study analyzing the use of ivermectin (2 doses, 300 µg/kg each, 72 hours apart) as prophylaxis found 73% reduction of COVID-19 infection among healthcare workers after 1 month follow-up. However, this study differs from ours in that ivermectin was used for prophylaxis and not treatment. A recent meta-analysis showed that ivermectin had limited benefit [odds ratio (OR) = 0.15, 95% confidence interval (CI) = 0.04–0.57]. Other meta-analysis (which included no RCT, only small observational studies) showed adding ivermectin led to significant clinical improvement compared to usual therapy (OR = 1.95, 95% CI = 1.09–3.49, P = 0.02). However, both these meta-analyses included observational studies in their ambit. When our study was conceived, there was limited literature on spontaneous COVID-19 resolution by days 7 and 8 of illness in Indian population. Hence, a presumed positivity rate of 100% was taken on discussion with microbiologists. However in our study, in the CG, we have found a positivity rate of 71.1% on day 3 (after recruitment) and 52.6 % on day 7. Future randomized double–blind placebo control studies may use this as a pilot and be undertaken on bigger sample sizes and higher doses.
Our study has an advantage of being a hospital based study, allowing close monitoring of patient symptoms, progress, and virologic clearance. Another highlight of our study is the inclusion of significant pediatric population (28.9%) in our study cohort. However, we only followed up the microbiologic clearance till 7 days after drug administration, and whether there is further divergence in results on further follow-up remains to be seen.
Our single center study shows that currently approved doses of ivermectin do not have any significant effect on symptom resolution, COVID-19 recovery, and Ct values. Further, multicenter adequately powered study with uniform outcome criterion across centers maybe needed. In the interim, self-medication with ivermectin should be discouraged, pending further robust data on prophylaxis and treatment benefit.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]