Briefing: Ivermectin (generic) C19-026

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RAPID-C19 Oversight Group
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1. Key considerations
Question Response Section
1. a) Where does ivermectin sit in the treatment pathway? b) Are there other treatments sitting in this place in the pathway? c) What is the mechanism of action of ivermectin that explains why it is being investigated as a potential treatment for COVID-19, and its particular place in the treatment pathway? d) Are there other treatments in this class (i.e with the same or similar mechanism of action) that have been considered by the Oversight Group and if so, what are these?
e) Are there other treatments in this class that are currently in clinical trials for COVID-19 and if so, what are they?
Prevention / mild / moderate / severe / critical / rehabilitation Y / N Please refer to the pathway diagram in the Oversight Group papers
Ivermectin is an antiparasitic drug with broad-spectrum antiviral activity. It acts by inhibiting the host importing alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host antiviral response. Ivermectin is therefore a host-directed agent, which is likely the basis for its broad- spectrum activity in vitro against the viruses that cause dengue, Zika, HIV, and yellow fever. Due to the broad spectral antiviral activities of ivermectin and it is safety profile, it may offer therapeutic potential in COVID-19. Ivermectin is also being investigated for use in prevention of COVID-19. Its virucidal effects are aimed at reducing the contagion. No No
5.1, 5.2, appendix 1 and 2
2. Is the evidence base sufficient to allow further action to be taken at this stage? Sufficient evidence base should take into account the amount of evidence (number of trials and total number of participants) as well as robustness of the trials.
Y / N 21 trials have reported results including 18
treatment trials, 2 prevention trials and 1 trial
for treatment and prevention. Of these, 6 are
in phase 3. The results of these trials have
been published in peer-reviewed journals,
5.1
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and significant methodological limitations.
• Some randomised controlled trials were open-label
• Patients received various concomitant therapeutics (e.g., doxycycline, hydroxychloroquine, azithromycin, zinc, corticosteroids) in addition to ivermectin or the comparator.
• The severity of COVID-19 in the study participants was not always well described.
• The study outcome measures were not always clearly defined.
3 Meta-analyses include RCTs with high risk of bias due to poor trial design. Most results show no statistical difference. This reduces the ability to draw any strong conclusions. Results from large robust trials are needed to confirm efficacy of ivermectin for treatment and prevention of COVID-19.
3. Is there a positive signal of efficacy across the outcomes?
Y / N / Unknown Some trials report positive results across key outcomes. However, these results are not robust due to small sample size, unclear methods, open-label, and many results not peer reviewed with some reported in the trial registry. Overall, there is a high risk of bias and low to moderate certainty of effect across all trials. 3 meta-analyses (Cochrane living meta- analysis, Dr Andrew Hill with International Ivermectin Project Team and Bryant et al., 2021) concluded that the evidence base for ivermectin is weak given the reasons stated above. The Dr Andrew Hill review and meta- analysis concluded that despite the encouraging trend this existing data base demonstrates, it is not yet a sufficiently robust evidence base to justify the use or regulatory approval of ivermectin.
5.1
5.1
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4. Is there a specific population where there could be significant benefit?
Y / N / Unknown Available evidence does not indicate whether there is a specific population of significant benefit.
5.1, appendix 1
5. Is there a signal of harm (including unfavourable effects and adverse events)?
Y / N There is currently no evidence indicating any signal of harm.
5.1, appendix 1
6. Are there other relevant issues for consideration (e.g. special populations of interest, regulatory issues, potential supply issues, service delivery or technology delivery challenges)?
Y / N / Unknown New Variants There is no information on which to consider the effectiveness of [the treatment] in treating COVID-19 caused by new variants of SARS- CoV-2. Regulatory Oral and injected ivermectin is unlicensed in the UK, if there is a positive result, supply issues are anticipated. Safety Merck advises to avoid Stromectol (ivermectin) in pregnancy and breastfeeding.
a
4
Next steps Stand down / monitor / progress Monitor for results from key trials reporting soon: NCT04446104 (prevention), n=4257, Singapore, PCD: 31/08/2020 (completed, no results)
Oversight Group 12/08/2020 Decision: Stand down / monitor / progress • Monitor with low interest
Oversight Group 21/10/2020 Decision: Stand down / monitor / progress
• Monitor with elevated interest for published results from Phase 3 trial (NCT04523831), Bangladesh, n=363 and other trials.
Oversight Group 10/03/2021 Decision: Stand down / monitor / progress
• Robust meta-analysis with high quality RCTs • Key trials
Progress: Oversight Group to take action (e.g. commission an evidence summary, begin regulatory discussions). Monitor: Oversight Group to reconsider topic at a later date (e.g. after trial results have published).
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Stand down: Oversight Group considers there is not, and is not likely to be, any positive signal that warrants further consideration of this topic. Source: a BNF
2. Treatment
Treatment Ivermectin
Type Anti-parasitic
Mechanism of action Ivermectin is a member of the avermectin class of broad spectrum antiparasitic agents. They cause the paralysis and death of parasites.
Administration Tablets, capsules and subcutaneous injection formulations are used in the COVID-19 trials (see appendix 2 for further details)
Dose and schedule Tablets: different doses and schedules are used in the trials: 0.2-0.6mg/kg once daily, 3-18mg once daily, 6-12mg twice a week and 12mg stat Capsules: 2-15mg/ day Subcutaneous injection: 200ug/kg Oral drops: 5 times daily for 14 days
Cost Unknown. Stromectol® 3 mg tablet is listed in the BNF as imported from France, but no price is available a
Existing guidance/information
On 05/03/2021 the FDA released a statement recommending against the used of ivermectin in COVID-19. They state:
• The FDA has not approved ivermectin for use in treating or preventing COVID-19 in humans.
• Ivermectin is not an anti-viral (a drug for treating viruses).
• Taking large doses of this drug is dangerous and can cause serious harm.
• Ivermectin should only be taken if patients have a prescription for an FDA-approved use, from a legitimate source and exactly as prescribed.
The NIH COVID-19 Treatment Guidelines Panel states there is insufficient data for the Panel to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well- conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19. CADTH produced a report on ivermectin to treat patients with COVID-19 infections. The report concluded that while some lab studies have shown ivermectin to be a promising treatment, it’s hard to know how well ivermectin works in patients because the included studies were not done well. The primary studies identified in the report, including those within the systematic review, had a high risk of bias. Therefore, the very low quality of evidence from the studies precludes the ability to draw any strong conclusions as to whether ivermectin can reduce all-cause mortality, improve clinical symptoms, hospitalisation and viral clearance.
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With the current evidence, the guidelines included in the report could not recommend the use of ivermectin for treatment of COVID-19. Ivermectin is being considered for addition into the PRINCIPLE trial. b
Source: a BNF, b Intelligence from the RAPID C-19 Oversight Group
3. Regulatory status
• Stromectol® tablets (Merck Sharp and Dohme) a.
• Ivera® tablets (Beximco Pharmaceuticals Ltd based in Bangladesh)
• Iverscab® tablets (NuLife based in India)
• Ivactin® tablets (Aristopharma Ltd based in Bangladesh)
A commercial sponsor for regulatory ownership of other oral or injected formulations has not yet been identified. ACTION: NHSE repurposing medicines group to [consider the appropriate time to] identify commercial sponsors wishing to pursue a license for COVID-19 via the British Generics Manufacturers Association (BGMA)
New or repurposed Repurposed
Branded or generic Generic
Regulatory status/plans COVID-19 Not yet licensed for COVID-19. Regulatory plans still to be confirmed with the companies. Existing indications in the UK Topical ivermectin has a licensed indication in the UK for papulopustular rosacea. Topical ivermectin has not been used in any trials to date. Oral ivermectin is unlicensed in the UK but is prescribed on a named patient basis for scabies.a
On 29 Sep 2020, MedinCell announced its intention to
submit a marketing authorisation application for ivermectin
long-acting injectable by early 2021
Ivermectin long-acting injectable (Medincell), in phase 1 trial
for COVID-19. b
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Ivermectin is likely to submit for or receive an EUA in the coming months as it is expected to hit clinical trial benchmarks by January 31 2021. c ACTION: NICE & MHRA to [consider the appropriate time to] gather additional information on regulatory plans from identified commercial sponsors
Source: a NICE Clinical Knowledge Summary, b MedinCell, c FCDO Services is part of the Foreign, Commonwealth & Development Office (FCDO) intelligence (03/12/2020)
4. Supply activities
Supply Stromectol® 3mg tablets are available in the UK imported from France a ACTION: Once a commercial sponsor is identified, DH Therapeutics Taskforce to [consider the appropriate time to] gather information from companies on supply and scale-up.
Source: a BNF
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5.1 Published evidence
The table below highlights the signals from the main published evidence and the strength of these signals, taking into account the magnitude of effect shown and the quality of the evidence. Any published studies not reporting key outcomes of interest or case studies are briefly summarised at the end of the table. Detailed information on all published studies are in appendix 1. 5.1.1 Evidence Table Table 1 Clinical trials
Study description Population Outcomes and results (intervention vs. comparator)
Evidence assessment*
Elgazzar et al., 2020 NCT04668469 Pre-print Phase unknown triple blinded RCT Egypt n=600 Treatment: ivermectin + SOC (azithromycin, paracetamol, vitamin c, zinc, lactoferrin, acetylcysteine) (n=200 (100 mild-moderate, 100 severe) Comparator: hydroxychloroquine + SOC (n=200 (100 mild- moderate, 100 severe)) Prophylaxis: ivermectin + personal protective measures (n=100) Comparator: personal protective measures (n=100 exposed)
Adults hospitalised with mild-moderate or severe symptoms and adults exposed to COVID-19 including health care (pre- exposure) and / or household (post- exposure) patients’ contacts
Primary outcomes: Number of participants with improvement of clinical condition (symptoms and signs) by 3 months. Mild-moderate: 99% vs. 74% Severe: 94% vs. 50% P<0.001 Primary outcomes: Reduction of recovery time, hospital stay days and mortality rate, by 3 months. Recovery time & Hospital stay (days) Mild-moderate: 4-6 (Mean SD - 5±1) vs. 6-31 (Mean SD 15±8) Severe: 4-7 (Mean SD 6±1) vs. 9-25 (Mean SD 18±8). P=<0.001 Mortality: Mild-moderate: 0% vs. 4% Severe: 2% vs. 20% P<0.001 Secondary outcome: Improvement of lab investigations and 2 consecutive negative PCR tests taken at least 48 hours apart, up to 3 months (RT- PCR conversion (days) mean ±SD) Mild-moderate: 5±1 vs. 10±4 Severe: 6±1 vs. 12±4 Prophylaxis. Confirmed infected subjects by RT-PCR. 2% vs. 10%. P<0.05
Precision Moderate Robustness Moderate-sized trial with limited concerns around risk of bias. However, results are not peer reviewed. Certainty of effect: moderate
Treatment
Adults with confirmed COVID-
Primary outcome: Mortality rate
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Pre-print Phase 1/2 single blinded RCT Iraq n=140 Treatment: ivermectin (tab) + doxycycline + SOC (n=70 (48 mild- moderate, 11 severe, 11 critical)) Comparator: standard care (n=70 (48 mild- moderate, 22 severe and 0 critical))
19 including outpatients with mild to moderate disease or patients hospitalised with confirmed or severe to critical disease.
Total: 2.85% (2/70) vs. 7.14% (6/70). P=0.14 (OR=0.31, P=0.16) Mild-moderate: 0% (0/48) vs. 0% (0/48). P=1. Severe: 0% (0/11) vs. 27.27%
(6/22). P=0.052 (OR=0.11,
P=0.14)
Critical: 18.2% (2/11) Primary outcome: Rate of progression to a more advanced stage of the disease Total: 4.28% (3/70) vs. 10%
(7/70). P=0.19
(OR=0.4, P=0.2) Mild-moderate: 0% (0/48) vs. 0% (0/48). P=1. Severe: 1/11 (9%) vs. 7/22 (31.81%). P= 0.15 (OR=0.21, P=0.17) Critical: 2/11 (18.2%)
Secondary outcome: Time to recovery (days) Total: 10.61± 5.3 vs. 17.9±6.8.
P <0.0001
Mild-moderate: 6.34±2.4 vs. 13.66±6.4. P <0.0001 Severe: 20.27±7.8 vs. 24.25±9.5. P=0.29. Critical: 19.77±9.2
Robustness RCT, however trial is small in size, single blinded, also results are not statistically significant and not yet peer reviewed. Certainty of effect: low
Mahmud et al., 2020 NCT04523831 Trial registry result Phase 3 double blinded RCT Bangladesh n=363 Treatment: ivermectin + doxycycline + SOC (183) Comparator: SOC (n=180)
Adult outpatients with confirmed mild to moderate COVID-19.
Primary outcome: Number of patients with early clinical improvement by day 7 60.7% (111/183) vs. 44.4% (80/180). P<0.03, Cox Proportional Hazard= 0.53, 95% CI= 0.30-0.96. Primary outcome: Number of participants with late clinical recovery (>12 days). 23% (42/183) vs. 37.2% (67/180). P<0.004, Cox Proportional Hazard= 0.51, 95% CI= 0.32-0.8. Secondary outcome: Number of patients having clinical deterioration up to 1 month. 8.7% (16/183) vs. 17.8% (32/180). P<0.0.13, Cox Proportional Hazard= 0.45, 95% CI= 0.23-0.85. Secondary outcome: Number of patients remain
Precision Moderate Robustness Reasonably sized RCT, but results only available on trial registry rather than reported in a peer-reviewed journal. Also, statistical significance of the result not reported. Certainty of effect: low/moderate
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persistently positive for rt- PCR of COVID-19. 7.7% (14/183) vs. 20% (36/180). P<0.001, Cox Proportional Hazard= 0.58, 95% CI= 0.44-0.81. All-cause mortality within 1 month: 0% (0/183) vs. 1.67% (3/180). Statistical significance unknown. Serious adverse events: 1.09% (2/183) vs. 0% (0/180) Statistical significance unknown.
Niaee et al., 2020 IRCT20200408046987N2 Pre-print Phase 2 double blind RCT Iran, 5 sites n=180 Treatment: ivermectin 1. single dose (200
mcg/kg). 2. 3 low doses (200
mcg/Kg) 3. single dose (400
mcg/Kg) 4. 3 high doses (400,
200, 200 mcg/Kg) Comparator: 5. SOC
(hydroxychloroquine) 6. Placebo + SOC
Adults hospitalised with mild to severe confirmed COVID- 19
Primary outcome: Duration of hospitalisation: 1. 6 [5 - 7] 2. 8 [6 - 9] 3. 5 [4 - 7] 4. 7 [6 - 10] 5. 7 [7 - 9] 6. 8 [6 - 11] 7. P=0.006 There was a decrease hospitalisation in ivermectin arms (arms 1-4) compared to the two untreated controls (arms 5-6) (P=0.006 and P=0.025 respectively). Mortality rate: 1. 0(0%) 2. 3 (10%) 3. 0 (0%) 4. 1 (3.3%) 5. 5 (16.7%) 6. 6 (20%) P=0.001 Risk of mortality in ivermectin group (3.3%, 95% CI 1.0%- 8.5%) vs. control (18.3%, 95% CI 10.4%-30.1%)
Precision Low Robustness Sample size is relatively small and results are not peer reviewed. Criteria for discharge changed during study from 2 negative PCRs to clinical recovery. Certainty of effect: moderate
Ravikirti et al., 2021 CTRI/2020/08/027225 (link unavailable) Pre-print Phase unknown double blind RCT India n=112
Adults hospitalised with mild and moderate COVID- 19.
Primary outcome: Negative RT-PCR report on day 6 23.6% (13/55) vs. 31.6 % (18/57). RR 0.8, 95% CI 0.4 to 1.4 P=0.347. Secondary outcome: In- hospital mortality no deaths in the ivermectin arm vs. 6.9% (n=4) in the placebo arm (RR 1.1, 95% CI 1.0 to 1.2 P=0.019).
Precision Low Robustness Sample size is relatively small and phase of study unknown. Also, results are not peer reviewed.
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Treatment: ivermectin (n=55) Comparator: placebo (n=57)
Secondary outcome: Asymptomatic by day 6 83.6% (46/55) vs. 89.5% (51/57) RR 0.9, 95% CI 0.8 to 1.1 P=0.363. Secondary outcome: Discharged by day 10: 80% (44/55) vs. 73.7% (42/57) RR 1.2, 95% CI 0.7 to 1.9 P=0.428. Discharge by end of study 100% (55/55) vs. 93% (53/57) RR 1.1, 95% CI 1.0 to 1.2 P=0.019. Secondary outcome: Need for invasive ventilation 1.8% (1/55) vs. 8.8% (n=5/57) RR 0.2, 95% CI 0 to 1.7 P=0.088. Secondary outcome: Admission to ICU 9.1% (5/55) vs. 10.5% (6/57) RR 0.9, 95% CI 0.3 to 2.7 P=0.798.
Certainty of effect: moderate
Lima-Morales et al., 2021 Trial link unknown Pre-print
Phase unknown open label trial Mexico n=768 Treatment: ivermectin, azithromycin, montelukast and acetylsalicylic acid (n=481) Comparator: `self- medicated for cold and flu symptoms` (n=287)
Adults ambulatory with confirmed mild to moderate COVID-19 disease
Mortality rate: 3.1% (15/481) vs. 18.1% (52/287) P=0.000 Risk of mortality: 81% lower risk of death with treatment. OR: 0.19. Days between onset of symptoms and recovery, mean (±SD) 10.5 (±5.8) TNR4 vs. 11.5 (±4.6) comparison, P=0.016 Percentage of recovered patients within 14 days: 84.4% (406/481) vs. 58.9% (169/287). P=0.000 Patients hospitalised (intubated or died): 9.1% (44/481) vs. 31% (89/287). P=0.000 Risk of being hospitalised: 75% lower with treatment OR: 0.25.
Precision Low Robustness Trial design unclear, phase unknown and open label. Not all patients received same drugs in treatment and comparator arms. 10.2% of those in treatment arm used other treatments including NSAIDs, cold and flu drugs, antivirals and antibiotics. Certainty of effect: very low
TrialSiteNews NCT04381884 Press release
Adults hospitalised with confirmed
Primary outcome: Reduction in SARS-CoV-2 viral load from days 1-5
Precision Low
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Phase 2 open label RCT Argentina n=45 Treatment: ivermectin + SOC (n=30) Comparator: SOC (n=15)
symptomatic mild to moderate COVID-19
ivermectin at a high dose (0.6 mg/kg) produced rapid viral elimination of the COVID-19 virus when started in the early stages of infection (up to 5 days from the onset of symptoms).
Robustness Open label design with a very small number of participants. Published results and statistical data required. Certainty of effect: very low
Babalola et al., 2021 ISRCTN40302986 (IVERCOVID) Published Phase 3 double blind RCT Nigeria n=62 Treatment: ivermectin + SOC 1. 6mg (n=21) 2. 12 mg (n=21) Comparator: 3. lopinavir/ ritonavir
(n=20)
Adults hospitalised with confirmed COVID- 19 and mild to moderate symptoms.
Primary outcome: Days to negative PCR test Arms 1 + 2: 5.33 (CI 4.33-6.32) 1. 6.0 (4.61 - 7.38) SD 2.96 2. 4.65 (CI 3.15- 6.15) SD 3.2 vs. 3. 9.15 (CI 5.68- 12.62), SD
3.12 P= 0.0066 ANOVA P>F= 0.017. Primary outcome: Treatment effect by RAMOVA Significant treatment (p=0.035) and time effect (p <0.0001) on COVID 19 ranked scores with ivermectin. Ivermectin arm 3.45 times more likely to go negative by or before day five. P=0.0271, 95% CI 1.12-10.63. This effect is slightly mitigated by sex (adjusted OR 3.44 P>z 0.031 CI= 1.12 -10.6) but more significantly by age (OR 2.77 P>z 0.113 CI= 0.79 to 9.8). Secondary outcomes: change in clinical status, change in SPO2, change in liver function tests, change in kidney function tests and change in rheological variables (platelet count, prothrombin time).
No statistically significant difference.
Precision Low Robustness Very small number of participants. Secondary outcomes showed no statistically significant difference. Certainty of effect: very low
Chaccour et al., 2021 NCT04390022 (SAINT) Published
Adults ambulatory with non-severe COVID-19
Primary outcome: Proportion of patients with a positive SARS-CoV-2 PCR 7 days post-treatment.
Precision Low Robustness
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Phase 2 double blind RCT Spain n=24 Treatment: ivermectin single dose (n=12) Comparator: placebo (n=12)
gene N 100% (12/12) and gene E 91% (11/12) vs. 100% (12/12) RR 0·92, 95% CI: 0·77–1 0·09, P = 1·0.
Very small number of participants. Statistically insignificant result. Certainty of effect: very low
López-Medina et al., 2021 NCT04405843 (EPIC) Published Phase 2/3 quadruple- blinded RCT n=389 Spain Treatment: ivermectin Stromectol (n=200) Comparator: placebo (n=198)
Adults ambulatory or hospitalised with mild COVID- 19 and symptoms for ≤7 days.
Primary outcome: Time to symptom resolution 10 days (IQR, 9-13) vs. 12 days (IQR, 9-13) Hazard ratio:1.07 [95% CI, 0.87 to 1.32]; P = 0.53 by log-rank test. Primary outcome: Rate of symptom resolution at day 21 82% (164/200) vs. 79% (156/198) OR, 1.23, [95% CI, 0.75 to 2.01] Secondary outcome: Deterioration by ≥2 points in an ordinal 8 point scale 2% (4/200) vs. 3.5% (7/198) OR, 0.56, [95% CI, 0.16 to 1.93] Secondary outcome: Fever since randomization 8% (16/200) vs. 10.6% (21/198) OR, 0.73, [95% CI, 0.37 to 1.45] Secondary outcome: Escalation of care since randomization 2% (4/200) vs. 5% (10/198) OR, 0.38, [95% CI, 0.12 to 1.24] Secondary outcome: Mortality 0% vs. 0.5% (1/198) Proportions of patients who sought medical care (ED or telemedicine consultation): 8.0% vs. 6.6% OR, 1.24 [95% CI, 0.56 to 2.74]
Precision Low Robustness The primary outcome changed from detection of clinical deterioration to symptom resolution at week 6. result. Certainty of effect: very low
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Adverse events up to day 21: 77% (154/200) vs. 81.3% (161/198)
Chachar et al., 2020 Trial source unknown Published
Phase unknown open label RCT. n=50 Pakistan Treatment: ivermectin + SOC (n=25) Comparator: SOC (n=25)
Adult outpatients with confirmed mild COVID-19.
Primary outcome: Symptom
Precision Low Robustness Very small number of participants. Statistically insignificant result. Trial phase unknown and open label design. Certainty of effect: very low
Mohan et al., 2021 Pre-print CTRI/2020/06/026001 RIVET-COV Phase 2/3 double blind RCT. n=125 India Treatment: Ivermectin elixir 24mg (n=40) Ivermectin elixir 12mg (n=40) Comparator: placebo (n=45)
Adults hospitalised with mild to moderate COVID-19.
Primary outcome: Conversion of RT-PCR to negative result at day 5 24 mg, 47.5% (3/40) 12 mg, 35.0% (14/40) vs. 31.1% (14/45). P=0.30 Subgroup analysis: Mild disease: 24 mg, 33.3% (8/24), 12 mg, 22.2% (6/27) vs. 24.1% (7/29). P=0.66 Moderate disease: Ivermectin 24 mg, 56.2% (9/16), 12 mg, 61.5% (8/13) vs. 43.8% (7/16). P=0.66 Primary outcome: Decline of viral load at day 5 of enrolment 12 mg, 3.05 (2.29), 24 mg, 3.04 (2.05) vs. 3.08 (1.98). P=0.99 Days to symptom resolution mean (SD) 12 mg, 4.26 (2.65), 24 mg, 4.76 (2.44) vs. 4.58 (2.94). P=0.77 Change in WHO Ordinal Scale score between daily 0- 14, n(%) Decrease by 1: 12 mg, 2.5%, 24 mg, 0% vs. 2.2% Decrease by 2: 12 mg, 87.5%, 24 mg, 80% vs. 82.2%. Decrease by 3: 12 mg, 5%, 24 mg, 12.5% vs. 4.4% P=0.67 Discharge by day 14, n(%)
Precision Low Robustness Small number of participants. Results demonstrated no significant difference. Certainty of effect: very low
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12 mg, 95%, 24 mg, 92.5% vs. 86.7%. P=0.42 Hospital-free days at day 28, mean (SD) 24 mg, 2.3%, 12 mg, 2% vs. 2%. P=0.79 Any clinical worsening (defined by progression in WHO ordinal scale during course of treatment, or need for escalation of care (e.g. new oxygen requirement) 24 mg, 7.5%, 12 mg, 5% vs. 11.1%. P=0.65 Total and serious adverse events All: 12 mg, 11.8%, 24 mg, 16.3% vs. 11.5%. P=0.76 Serious: 12 mg, 0%, 24 mg, 0%, vs. 0%
Okumus et al., 2021 NCT04646109 Trial registry result Phase 3 open label RCT
n=60
Adults hospitalised with severe COVID-19.
Primary outcome: Number of Participants With Clinical Response by day 5 (at least 2 of: extubation in mechanically ventilated patients, respiratory rate <26/min, SpO2 level in room air >90%, PaO2/FiO2 >300 in patients receiving oxygen, presence of at least two of the 2-point reduction criteria in "Sequential Organ Failure Assessment (SOFA)" score). 36.7% (11/30) vs. 46.7% (14/30). P=0.43 Primary outcome: Changes in Oxygen Saturation (SpO2) Values by day 5, mean (SD). Baseline: 89.67 (5.09), day 5: 93.00 (3.25) vs. baseline: 89.93 (6.51), day 5: 93.52 (4.36). P=0.03 Primary outcome: Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) by day 5, mean (SD). Baseline: 197.44 (102.31), day 5: 180.13 (95.43) vs. baseline: 158.83 (88.15), day 5: 178.94 (98.21). P=0.39.
Precision Low Robustness Very small number of participants. Most results demonstrated no significant difference. Open label design. Certainty of effect: very low
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Primary outcome: Treatment- Related Adverse Events as Assessed by CTCAE v4.0 by day 5 Nausea and vomiting: 6.7% vs. 0% Increase in liver function tests: 3.3% vs. 0%. Secondary Outcome: Mortality up to 3 months 30.3% (9/30) vs. 20% (6/30). P=0.37 Secondary Outcome: Number of Participants With Clinical Response after 5 days treatment and 5 days follow up. 36.7% vs. 46.7%. P=0.43
Podder et al., 2020 Published Trial source unknown Phase unknown open label RCT n=62
Bangladesh.
Comparator: SOC (n=30)
Adult outpatients with mild to moderate confirmed COVID- 19.
Primary outcome: Time to complete symptom resolution 5.31±2.48 vs. 6.33±4.23. P>0.05 [95% CI, -0.766 to 2.808] Primary outcome: Negative repeat RT-PCR test by day 10. 90% vs. 85%. P>0.05
Precision Low Robustness Very small number of participants. Results demonstrated no significant difference. Open label design and details of SOC unknown. Certainty of effect: very low
Prevention
Shouman et al., 2020 NCT04422561 Trial registry result Phase 2/3 open label RCT n=304 Egypt Intervention: ivermectin tablets (n=203) Comparator: no intervention (observation) (n=101)
Asymptomatic family close contact of confirmed COVID -19 patient.
Primary outcome: Development of Symptoms by day 14 7.4% vs. 58.4% All-cause mortality 0% vs. 0% Serious adverse events 0% vs. 0%
Precision Low Robustness Statistical data not reported and result via trial registry. Open label design. Certainty of effect: very low
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*Explanation of the certainty of the effect based on the precision of the estimates and the robustness of the evidence High certainty Very confident that the true effect lies close to that of the estimate of the effect Moderate certainty Moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty Confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty Very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
Table 2 Meta-analyses
Evidence assessment*
Cochrane meta-analysis
Cochrane meta-analysis Living meta- analysis 9 RCTs (sample size ranged from 24 to 180) n=778 Bangladesh, Argentina, Spain, Pakistan, India, Iran Treatment: ivermectin Comparator: placebo or SOC
Adult outpatients and hospitalised with mild, moderate and severe COVID-19
All-cause mortality by day 28 (results based on 6 RCTs) 1.2% (4/343) vs. 5.4% (12/221) RR: 0.19 (85% CI: 0.07 to 0.55) Absolute: 44 fewer per 1,000 (95% CI, from 50 fewer to 24 fewer) WHO progression score (level 7 or above) by day 28 (results based on 4 RCTs) 1/166 vs. 0/103 RR: 1.55 (95% CI: 0.07 to 35.89) Clinical improvement by day 28 (results based on 3 RCTs) 74.2% (135/182) vs. 71.1% (96/135) RR: 1.03 (0.90 to 1.18) Absolute: 21 more per 1,000 (from 71 fewer to 128 more) Viral negative conversion by day 7 (results based on 7 RCTs) 49.6% (112/226) vs. 45.8% (97/212) RR: 1.00 (95% CI: 0.86 to 1.16) Absolute: 0 fewer people per 1,000 (from 64 fewer to 73 more)
(forest plots in the next section)
Precision Cochrane states serious imprecision for all outcomes and very serious imprecision for WHO progression score Robustness Cochrane rated risk of bias for all outcomes as serious Certainty of effect: Low to Very Low Cochrane rated low across all outcomes and very low for WHO progression score
Other meta-analyses
Dr Andrew Hill with International Ivermectin Project Team Pre-print, Jan 2021 UPDATE 01/03/2021 Additional slides with trial
Adults with mild/ moderate and severe disease, hospitalised or outpatients, with and without symptoms.
• 11 RCTs investigate mild to moderate severity.
Survival In 6 RCTs of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52]; P=0.0002) 2.1% (14/658) vs. 9.5% (57/597) Effects on Inflammatory Markers (CRP, ferritin, d-dimer) 4 trials demonstrated significant reductions in CRP compared to control.
PCR negativity (viral clearance)
Precision Low Robustness Many trials not yet published or peer reviewed. Wide variation in standard of trials, comparability of data limited. ivermectin dose and duration of
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investigating viral load 18 RCTs, 12 single/double blinded and 6 open-label. 5 published papers, 6 pre- prints, 6 unpublished papers, 1 trial registry result
n=12282 (sample size of included RCTs range from 24 to 400) Egypt, Bangladesh, Iran, Iraq, Argentina, Spain Treatment: Ivermectin single dose (9 trials) Ivermectin multi day dosing up to 7 days (9 trials (3 dose ranging)) Comparator: SOC
The effects of ivermectin on viral clearance were generally smaller when dosed on only one day. Several studies showed no statistically significant effect of ivermectin on viral clearance
Clinical recovery 4 of 6 trials showed significantly faster time to
clinical recovery on ivermectin compared to
control. In five trials, ivermectin showed
significantly shorter duration of hospitalisation
compared to control
Hospitalisation Ivermectin showed significantly shorter duration of hospitalisation compared to control.
The authors concluded that despite the encouraging trend this existing data base demonstrates, it is not yet a sufficiently robust evidence base to justify the use or regulatory approval of ivermectin.
treatment was heterogeneous. Many trials open label. Meta- analysis not peer reviewed. SOC differed between trials, ivermectin often given in combination with doxycycline or other antimicrobials.
Certainty of effect: low Meta-analysis assessed for risk of bias using the Cochrane Collaboration risk of bias standardized assessment tool. 11 trials were of poor quality and 7 of fair or high quality.
Bryant et al., 2021 Pre-print n=2741
(sample size
of included
RCTs ranged
• 4 RCTs investigated severe disease.
Primary outcome, mortality (n=1892) Ivermectin reduced the risk of death by an average of 68% (95% CI, 28% to 86%) compared with no ivermectin treatment (average risk ratio (aRR) 0.32, 95% CI 0.14 to 0.72; I2= 57%; risk of death 2.5% versus 9.1% among hospitalised patients in this analysis, respectively. Secondary outcomes Low certainty findings suggested no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ favoured ivermectin. Adverse events (n=728) Meta-analysis of 8 trials, found that there was no significant difference between ivermectin
Precision Low Robustness Many trials not yet published or peer reviewed. Quality of trials very low to moderate. Many trials open label. Meta- analysis not peer reviewed. SOC differed between trials, ivermectin often given in combination
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Intervention: ivermectin Comparator: placebo or no ivermectin. 4 trials included an active comparator.
and control in the risk of severe adverse events, aRR 3.23, 95% CI 80.55 to 18.87; I2= 0%. Prophylaxis (n=738) Ivermectin prophylaxis among health care workers and COVID-19 contacts probably reduces the risk of COVID-19 infection by an average of 86% (79% to 91%) (3 trials, 738 participants; aRR 0.14, 95% CI 0.09 to 0.21; 5.0% vs 29.6% contracted covid-19, respectively.
with doxycycline or other antimicrobials. Certainty of effect: low This meta- analysis was done using Cochrane methods. Evidence was assessed using the GRADE approach. Evidence was graded low-to moderate overall.
*Explanation of the certainty of the effect based on the precision of the estimates and the robustness of the evidence High certainty Very confident that the true effect lies close to that of the estimate of the effect Moderate certainty Moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty Confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty Very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
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Figure 1: Mortality
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5.2 Ongoing trials
• There are 86 active trials investigating ivermectin in COVID-19 for treatment and prevention of mild, moderate and severe disease.
• Active trials include 10 prevention trials, 73 treatment trials and 4 trials investigating prevention and treatment of COVID-19.
• 44 trials are recruiting, 26 trials are not yet recruiting, and 12 trials have completed with no results available.
• Of the 44 trials that are recruiting, there is a total target enrolment of 11,028 patients, however the majority of trials are small with 20 trials enrolling 100 or less patients.
• There is only 1 trial recruiting in the UK, an exploratory phase 1 placebo-controlled RCT, enrolling only 24 patients.
• Ivermectin is being considered for addition into the PRINCIPLE trial.
5.2.1 Key trials
The table below shows the key trials (in UK and NIHR-prioritised if applicable) that are likely
to impact on decision-making (because of robust trial design and reporting of key outcomes):
Treatment and Prevention PaTS-COVID/ NCT04703608/ PACTR202101544570971 (London School of Hygiene and Tropical Medicine sponsored phase 3 RCT)
• Estimated enrollment: 1200
• Primary outcomes: Viral transmission and worsening disease severity.
• Estimated PCD: 01/03/2022
• Population: Outpatient Treatment of Patients With Early-Onset COVID-19 and Mild Symptoms
• Primary outcomes: To evaluate the effect of fluvoxamine, ivermectin and metformin in reducing need for emergency care and observation for more than 12 hours due to the worsening of COVID-19.
• Estimated PCD: 01/02/2022
• Estimated PCD: 31/08/2020 (completed, no results)
ISRCTN90437126 (Federal University of Pernambuco funded phase 3 RCT)
• Primary outcomes: COVID-19 case diagnosis
• Estimated PCD: Unknown
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ACTION: NICE to contact principle investigators using standard RAPID C-19 template letter to request more information on earliest anticipated reporting dates if possible, and whether key signals/results can be provided in advance of publication.
Further details of these trials are presented in appendix 2 and 3.
5.2.2 Trials expected to report soon
The table below shows the trials due to report soon that are reasonably well designed and powered and/or investigating relevant clinical outcomes of interest:
Design Size Location Primary outcome(s)
Estimated PCD
31/01/2021 Completed
31/03/2021
01/05/2021
Prevention
NCT04446104 RCT
NCT04384458 RCT
10/09/2020
Further details of these trials are presented in appendix 2.
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Reference Design of study Population Results
Cochrane meta- analysis Living meta- analysis
9 RCTs (sample size ranged from 24 to 180) n=778 Bangladesh, Argentina, Spain, Pakistan, India, Iran Treatment: ivermectin Comparator: placebo or SOC
Adult outpatients and
severe COVID-19
All-cause mortality by day 28 (results based on 6 RCTs) 1.2% (4/343) vs. 5.4% (12/221) RR: 0.19 (85% CI: 0.07 to 0.55) Absolute: 44 fewer per 1,000 (95% CI, from 50 fewer to 24 fewer) WHO progression score (level 7 or above) by day 28 (results based on 4 RCTs) 1/166 vs. 0/103 RR: 1.55 (95% CI: 0.07 to 35.89) Clinical improvement by day 28 (results based on 3 RCTs) 74.2% (135/182) vs. 71.1% (96/135) RR: 1.03 (0.90 to 1.18) Absolute: 21 more per 1,000 (from 71 fewer to 128 more) Viral negative conversion by day 7 (results based on 7 RCTs) 49.6% (112/226) vs. 45.8% (97/212) RR: 1.00 (95% CI: 0.86 to 1.16) Absolute: 0 fewer people per 1,000 (from 64 fewer to 73 more)
Bryant et al., 2021 Pre-print
21 RCT`s involving (sample
sizes ranging from 24 to 363
participants. 13 (n=1892)
trials contributed data for
blinding.
COVID-19.
Primary outcome, mortality (n=1892): Ivermectin reduced the risk of death by an average of 68% (95% CI, 28% to 86%) compared with no ivermectin treatment (average risk ratio (aRR) 0.32, 95% CI 0.14 to 0.72; I2= 57%; risk of death 2.5% versus 9.1% among hospitalised patients in this analysis, respectively. Low to moderate certainty. Secondary outcomes: Low certainty findings suggested no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ favoured ivermectin. Low to very low certainty evidence. Adverse events (n=728): Meta-analysis of 8 trials, found that there was no significant difference between ivermectin and control in the risk of severe adverse events, aRR 3.23, 95% CI 80.55 to 18.87; I2= 0%. Low certainty of evidence.
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Comparator: placebo or no ivermectin; 4 trials included an active comparator.
Prophylaxis (n=738): ivermectin prophylaxis among health care workers and COVID-19 contacts probably reduces the risk of COVID-19 infection by an average of 86% (79% to 91%) (3 trials, 738 participants; aRR 0.14, 95% CI 0.09 to 0.21; 5.0% vs 29.6% contracted covid-19, respectively. Low certainty of evidence
CADTH report CADTH report on ivermectin to treat patients with COVID- 19 infections. Systematic review of 4 observational studies, 3 with a control arm and 1 without a control arm. Primary studies included 1 RCT (n=72), 1 retrospective chart review (n=26) and 1 retrospective database review. India, Bangladesh, Spain, US, Australia.
Adults hospitalised with mild, moderate and severe, symptomatic or asymptomatic COVID- 19.
The primary studies identified in this report including those within the systematic review were found to have high risk of bias, thus producing a very low quality of evidence that preclude the ability to draw any strong conclusions as whether ivermectin could reduce all-cause mortality, improve clinical symptoms and hospitalisation, and enhance viral clearance in patients with COVID-19.
Castañeda- Sabogal et al. 2020
Systematic review and meta- analysis of twelve studies (5 retrospective cohort studies, 6 randomised clinical trials and 1 case series), was carried out to assess the outcomes of ivermectin in ambulatory and hospitalised patients with COVID-19.
7412 participants were reported, the mean age was 47.5 (SD 9.5) years, and 4283 (58%) were male
• Ivermectin was not associated with reduced mortality (logRR: 0.89, 95%
CI 0.09 to 1.70, p = 0.04, I2= 84.7%), or reduced patient recovery
(logRR 5.52, 95% CI -24.36 to 35.4, p = 0.51, I2 = 92.6%). All studies
had a high risk of bias, and showed a very low certainty of the evidence.
• Overall, based on this analysis there is insufficient certainty and quality of evidence to recommend the use of ivermectin to prevent or treat ambulatory or hospitalised patients with COVID-19.
Mohanty et al., 2020
Systematic review and meta- analysis to assess available data on the therapeutic potential of ivermectin for the treatment of COVID19 as add on therapy.
397 RT-PCR confirmed COVID-19 adult patients of both genders treated with ivermectin as an add-
• Primary outcomes were all-cause mortality and any death during the available period of follow up in the studies. Secondary outcomes were 1) time to discharge from the hospital, 2) time to viral clearance by PCR, 3) clinical improvement assessed by the need for respiratory support.
• The random effect model showed the overall pooled odds ratio (OR) to be 0.53 (95%CI: 0.29 to 0.96) for the primary outcome (all-cause
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The 4 observational studies reviewed included: Gorial et al., 2020 Rajter et al., 2020 Chowdury et al., 2020 Bhattacharya et al., 2020
on therapy were included in the study.
mortality) which was statistically significant (P=0.04). Similarly, the random effect model revealed that adding ivermectin led to significant clinical improvement compared to usual therapy (OR=1.98, 95% CI: 1.11 to 3.53, P=0.02). However, this should be inferred cautiously as the quality of evidence is very low.
UPDATE 01/03/2021 Additional slides with trial investigating viral load
Dr Andrew Hill of the Department of Pharmacology at the University of Liverpool (UK) and the International Ivermectin Project Team Preliminary results, Dec 2020
Systematic review and meta- analysis of randomised controlled trials of ivermectin against COVID. 18 RCTs, 12 single/double blinded and 6 open-label 5 published papers, 6 pre- prints, 6 unpublished papers, 1 trial registry result Egypt, Bangladesh, Iran, Iraq, Argentina, Spain Treatment: Ivermectin single dose (9 trials) Ivermectin multi day dosing up to 7 days (9 trials (3 dose ranging)) Comparator: SOC
Adults with mild/ moderate (11 RCTs) and severe disease, hospitalised or outpatients, with and without symptoms.
Survival In 6 RCTs of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52]; P=0.0002) 2.1% (14/658) vs. 9.5% (57/597) Effects on Inflammatory Markers (CRP, ferritin, d-dimer) 4 trials demonstrated significant reductions in CRP compared to control.
PCR negativity (viral clearance) The effects of ivermectin on viral clearance were generally smaller when dosed on only one day. Several studies showed no statistically significant effect of ivermectin on viral clearance
Clinical recovery 4 of 6 trials showed significantly faster time to clinical recovery on ivermectin
compared to control. In five trials, ivermectin showed significantly shorter
duration of hospitalisation compared to control
Hospitalisation Ivermectin showed significantly shorter duration of hospitalisation compared to control.
Source: NICE Information Services literature search (04/03/2021)
Abbreviations: PCR, polymerase chain reaction
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Population Results
Treatment
IMC Journal of Medical Science Podder et al., 2020 Published Ivermectin oral
Phase unknown open label
confirmed COVID-19.
Primary outcome: Time to complete symptom resolution 5.31±2.48 vs. 6.33±4.23. P>0.05 [95% CI, -0.766 to 2.808] Primary outcome: Negative repeat RT-PCR test by day 10. 90% vs. 85%. P>0.05
Okumus et al., 2021 NCT04646109 Trial registry result Ivermectin oral
Phase 3 open label RCT.
Turkey.
between 36-50 kg, 12 mg
between 51-65 kg, 15 mg
between 66-79 kg and 200
microgram/kg in > 80 kg) +
with severe COVID-19.
Primary outcome: Number of Participants With Clinical Response by day 5 (at least 2 of: extubation in mechanically ventilated patients, respiratory rate <26/min, SpO2 level in room air >90%, PaO2/FiO2 >300 in patients receiving oxygen, presence of at least two of the 2-point reduction criteria in "Sequential Organ Failure Assessment (SOFA)" score). 36.7% (11/30) vs. 46.7% (14/30). P=0.43 Primary outcome: Changes in Oxygen Saturation (SpO2) Values by day 5, mean (SD). Baseline: 89.67 (5.09), day 5: 93.00 (3.25) vs. baseline: 89.93 (6.51), day 5: 93.52 (4.36). P=0.14 Primary outcome: Changes in the Ratio of Partial Pressure of Oxygen (PaO2) to Fraction of Inspired Oxygen (FiO2) (PaO2/FiO2) by day 5, mean (SD). Baseline: 197.44 (102.31), day 5: 180.13 (95.43) vs. baseline: 158.83 (88.15), day 5: 178.94 (98.21). P=0.68. Primary outcome: Treatment-Related Adverse Events as Assessed by CTCAE v4.0 by day 5 Nausea and vomiting: 6.7% vs. 0%
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Population Results
Increase in liver function tests: 3.3% vs. 0% Secondary Outcome: Mortality 30.3% (9/30) vs. 20% (6/30) Secondary Outcome: Number of Participants With Clinical Response after 5 days treatment and 5 days follow up. 53.3% vs. 73.3%
ResearchSquare Mohan et al., 2021 Pre-print CTRI/2020/06/026001 RIVET-COV Ivermectin oral
Phase 2/3 double blind RCT.
India.
Placebo (n=45)
88.8% males.
Primary outcome: Conversion of RT-PCR to negative result at day 5 24 mg, 47.5% (3/40) 12 mg, 35.0% (14/40) vs. 31.1% (14/45). P=0.30 Subgroup analysis based upon disease severity also demonstrated no significant difference in the negativity of RT- PCR at day 5. Mild disease: 24 mg, 33.3% (8/24), 12 mg, 22.2% (6/27) vs. 24.1% (7/29). P=0.66 Moderate disease: Ivermectin 24 mg, 56.2% (9/16), 12 mg, 61.5% (8/13) vs. 43.8% (7/16). P=0.66 Primary outcome: Decline of viral load at day 5 of enrolment 12 mg, 3.05 (2.29), 24 mg, 3.04 (2.05) vs. 3.08 (1.98). P=0.99 Days to symptom resolution mean (SD) 12 mg, 4.26 (2.65), 24 mg, 4.76 (2.44) vs. 4.58 (2.94). P=0.77 Change in WHO Ordinal Scale score between daily 0-14, n(%) Decrease by 1: 12 mg, 2.5%, 24 mg, 0% vs. 2.2% Decrease by 2: 12 mg, 87.5%, 24 mg, 80% vs. 82.2%. Decrease by 3: 12 mg, 5%, 24 mg, 12.5% vs. 4.4% P=0.67 Discharge by day 14, n(%) 12 mg, 95%, 24 mg, 92.5% vs. 86.7%. P=0.42 Hospital-free days at day 28, mean (SD) 24 mg, 2.3%, 12 mg, 2% vs. 2%. P=0.79
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Population Results
Any clinical worsening (defined by progression in WHO ordinal scale during course of treatment, or need for escalation of care (e.g. new oxygen requirement) 24 mg, 7.5%, 12 mg, 5% vs. 11.1%. P=0.65 Total and serious adverse events All: 12 mg, 11.8%, 24 mg, 16.3% vs. 11.5%. P=0.76 Serious: 12 mg, 0%, 24 mg, 0%, vs. 0%
ResearchGate Krolewiecki et al., 2020 Published NCT004381884 (link unavailable) Ivermectin oral
Phase 1 open label RCT.
Argentina.
Primary outcome: Viral load reduction in respiratory secretions at day-5.
• There was no difference in viral load reduction between groups but a significant difference in reduction was found in patients with higher median plasma ivermectin levels (72% IQR 59 – 77) versus untreated controls (42% IQR 31 – 73) (p=0·004).
• The mean ivermectin plasma concentration levels also showed a positive correlation with viral decay rate (r:0·47, p=0·02).
Adverse events
• 5 (33%) patients in the controls and 13 (43%) in the ivermectin treated group, without a relationship between ivermectin plasma levels and adverse events.
International Journal of Sciences Chachar et al., 2020 Published Ivermectin oral
Phase unknown open label
mg after 12 hours and 12mg
after 24 hours + SOC (n=25)
Control (SOC) (n=25)
50 adult (18-75 years)
(38%) females.
asymptomatic by day 7. P=0.500
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Population Results
Phase 2/3, quadruple-blind,
randomised trial. Colombia.
days or placebo.
hospitalised).
Primary outcome: time to resolution of symptoms within a 21-
day follow-up period.
Median time to resolution of symptoms:
• 10 days (IQR, 9-13) in the ivermectin group compared with 12
days (IQR, 9-13) in the placebo group (hazard ratio for
resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = 0.53 by
log-rank test).
• By day 21, 82% in the ivermectin group and 79% in the placebo
group had resolved symptoms.
received placebo.
failure, occurring in 4 patients (2 in each group).
Conclusion: Among adults with mild COVID-19, a 5-day course of
ivermectin, compared with placebo, did not significantly improve the
time to resolution of symptoms. The findings do not support the use
of ivermectin for treatment of mild COVID-19.
International Journal of Infectious Diseases Lima-Morales et al., 2021 Pre-print Trial source unavailable Ivermectin oral
Comparative effectiveness
(ivermectin 12mg single dose,
moderate lab
confirmed COVID-19
• Days from symptom onset to recovery: 10.5 (±5.8) TNR4 vs.
11.5 (±4.6) comparison, P=0.016
• Percentage of recovered patients within 14 days: 84.4%
(406/481) TNR4 vs. 58.9% (169/287) comparison, P=0.000
• Participants in the TNR4 group had a 3.4 times greater
likelihood of making a full recovery, than those in the
comparison group.
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Population Results
who received the TNR4
1.4% took one medication.
comparison group 41.2%)
o Older participants between 49 to 80 years (TNR4 76.4%
versus comparison group 45.4%),
60.5%)
Hospitalisation:
comparison), P=0.000
lower among those who took TNR4 therapy, than in the
comparison group. This was observed in all sub-groups (p
values ≤0.010, in all groups).
• The risk of being hospitalised was 75% lower among
participants treated with TNR4 (OR: 0.25)
Mortality:
P=0.000
lower among the TNR4 treatment than in the comparison group
for all sub-groups: patients with comorbidities, older participants,
males, and health workers (p≤0.027 in all groups).
• Patients treated with TNR4 had an 81% lower risk of death
among the total study population (OR: 0.19).
Adverse events:
medications were reported by 354 participants, and most
participants did not experience any side effects from any of
the drugs (88.7%)
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Population Results
Ivermectin tablet
Phase 1, open-label, non- randomised trial. Egypt. Patients were randomised to
a combination of antivirals
treatment (n=52)
(paracetamol, zinc, good
nutrition, hydration and
by case.
• 90-120 kg 4 tables (300- 400 ug/kg)
• >120 kg 5 tables (30 mg)
113 adult outpatients
with confirmed COVID-
moderate disease
Primary outcome: rate and time of viral clearance
• Viral clearance rates were: o Day 7: 0% (supportive care) and 58.1% (anti-virals)
P≤0.001 o Day 15: 13.7% (supportive care) and 73.1% (anti-virals)
P≤0.001 o Day 15 cumulative clearance rates: 13.7 (supportive
care) and 88.7% (anti-virals) P≤0.001 Adverse events:
• The most common side effects were GIT upsets, coloured urine and palpitation (22.6%, 22.6% and 19.4%).
• No mortality was recorded during the follow-up duration (15 days).
Limitations:
• Both groups were matched in their age, sex, residence and CT
lung findings. However, patients on supportive treatment are
more likely to be health care workers, unknown exposure, early
moderate severity and have low mean oxygen saturation than
the other group.
The trial concluded that combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively clear the SARS- COV2 from nasopharynx in shorter time than the symptomatic therapy.
Association of Physicians of Great Britain and Ireland Babalola et al., 2021 ISRCTN40302986 (IVERCOVID)
Phase 3, Randomised, Controlled, Parallel Assignment trial. Nigeria. Patients were randomised to 3 treatment groups. All groups plus standard of care. 1. ivermectin 6mg regime
62 adult patients with
Recovery
• The days to COVID negativity was dose dependently reduced by ivermectin (p = 0.0066).
• Mean days-to-negative in the control arm was 9.15 (CI 5.68 to 12.62) while for combined Ivermectin arms it was 5.33 (CI 4.33 to 6.32), therefore shorter by 3.83 days (95% CI 6.54 to 1.11) compared to controls P=0.0066. (Student t-test.)
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Population Results
Ivermectin tablet 2. ivermectin 12 mg regime (given every 84 hours for 2 weeks)
3. lopinavir/ritonavir (control)
five required intranasal
control arm).
Average age:
44.1years (SD14.7),
and 19 females.
• Mean days-to-negative for the 12mg arm was however shortened by 4.5 days, and by 3.15 days for the 6mg arm compared to controls. These differences were significant by ANOVA (Analysis Of Variance) P>F=0.0179.
• 2 Way repeated measures ANOVA of ranked COVID 19 +/- scores at 0, 84, 168, 232 hours showed a significant ivermectin treatment effect (p = 0.035) and time effect (p < 0.0001).
• Ivermectin also tended to increase SPO2% compared to controls, p = 0.073, 95% CI - 0.39 to 2.59
• Ivermectin increased platelet count compared to C (p = 0.037) 95%CI 5.55 - 162.55 × 103/ml. The platelet count increase was inversely correlated to days to COVID negativity (r = -0.52, p = 0.005).
Adverse events: No serious adverse events were reported.
The Lancet Chaccour et al., 2021 NCT04390022 (SAINT) Ivermectin tablet
Phase 2, Randomised, Parallel Assignment, Trial. Spain. Patients were randomised 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12).
24 patients with non- severe COVID-19 and no risk factors for complicated disease attending the emergency room. All enrollments occurred within 72 h of onset of fever or cough. Median age, 26 [IQR 19–36 in the ivermectin and 21–44 in the controls] years; 12 (50% women
Primary outcome: measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment.
• Primary outcome: There was no difference in the proportion of PCR positive patients at day 7 post treatment, 12/12 (100%) patients had a positive PCR for gene N in both groups. For gene E, 11/12 (91%) in the ivermectin and 12/12 (100%) in the placebo group had a positive PCR (RR 0·92, 95% CI: 0·77–1 0·09, p = 1·0).
• Viral load:
• Genes E and N had comparable results at all time points
• the median viral load for both genes was lower at days 4 and 7 post treatment in the ivermectin group with differences increasing from 3-fold lower at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) to around 18-fold lower at day 7 (p = 0·16 for gene E; p = 0·18 for gene N)
• Adverse events: Patients in the ivermectin group reported fewer patient-days of any symptoms than those in the placebo group (171 vs 255 patient-days). This difference is mostly driven by two symptoms, anosmia/hyposmia and cough.
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Population Results
Mahmud et al., 2020 NCT04523831 Results only available in the trial registry Ivermectin tablet
Phase 3, Double blinded, Parallel Assignment, Randomised, Controlled trial. Bangladesh. Patients randomised to ivermectin + doxycycline + SOC (n=183) or SOC (n=180)
363 adult patients with mild to moderate disease
Primary outcomes:
• Number of patients have clinical improvement as described by WHO and Bangladesh local guideline within 7 days - ivermectin + doxycycline + SOC (111/183 (60.7%)) vs placebo + SOC (80/180 (44.4%)), p<0.03, Cox Proportional Hazard= 0.53, 95%CI= 0.30-0.96
• Number of Participants With Late Clinical Recovery (more than 12 days for clinical improvement - ivermectin + doxycycline + SOC (42/183 (23%)) vs placebo + SOC (67/180 (37.2%)), p<0.004, Cox Proportional Hazard= 0.51, 95%CI= 0.32-0.8
Secondary outcomes:
• Number of patients deteriorating to next level of severity (from mild-moderate to moderate, severe or death) within 1 month - ivermectin + doxycycline + SOC (16/183 (8.7%)) vs placebo + SOC (32/180 (17.8%)), p<0.13, Cox Proportional Hazard= 0.45, 95%CI= 0.23-0.8
Number of patients positive for RT-PCR of COVID-19 at day 14 after the day of initial positivity - ivermectin + doxycycline + SOC (14/183 (7.7%)) vs placebo + SOC (36/180 (20%)), p<0.001, Cox Proportional Hazard= 0.58, 95%CI= 0.44-0.81
TrialSiteNews Press release
n=45 (30 ivermectin, 15 control)
ivermectin + SOC vs SOC
45 adult patients hospitalised with confirmed symptomatic mild to moderate COVID-19
Primary outcome: Reduction in SARS-CoV-2 viral load from days 1- 5. Ivermectin at a high dose (0.6 mg/kg) produced rapid viral elimination of the COVID-19 virus when started in the early stages of infection (up to 5 days from the onset of symptoms).
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Population Results
Pilot Trial – Phase 1, synthetic-controlled arm (Historic control) study. Bagdad. Ivermectin and Hydroxychloroquine and Azithromycin vs Hydroxychloroquine and Azithromycin
87 adults aged 18 years+ hospitalised with confirmed COVID- 19 and pneumonia Patients had adequate hepatic and renal function with weight >15kg.
Primary endpoint, number of cured patients (symptoms free to be discharged from the hospital and 2 consecutive negative PCR test)
• All the patients in the ivermectin group were cured compared with the controls [16 (100 %) vs 69 (97.2%)]. Two patients died in the controls.
Secondary endpoint, Mean time to cure of the COVID-19 patients
• The mean time to stay in the hospital was significantly lower in Ivermectin group compared with the controls (7.62 ± 2.75 versus 13.22 ±5.90 days, p=0.00005, effect size= 0.82).
No adverse events were observed
medRxiv Hashim et al. 2020 Pre-print NCT04591600 Ivermectin capsule
Phase 1/2 randomised, parallel assignment, single blind, controlled trial. Baghdad, Iraq. Patients on treated with doxycycline and 200ug/kg of Ivermectin per day for 2-3 days plus standard therapy vs. standard therapy.
Treatment arm: 70 COVID-19 patients (48 mild-moderate, 11 severe, and 11 critical patients) Control arm: 70
COVID-19 patients (48
mild-moderate and 22
therapy.
• The time to recovery, the progression of the disease, and the mortality rate were the outcome-assessing parameters.
• Among all patients and among severe patients, 3/70 (4.28%) and 1/11 (9%), respectively progressed to a more advanced stage of the disease in the Ivermectin-Doxycycline group 7/70 (10%) and versus the control group 7/22 (31.81%), P>0.05.
• The mortality rate was 0/48 (0%), 0/11 (0%), and 2/11 (18.2%) in mild-moderate, severe, and critical COVID-19 patients, respectively in Ivermectin-Doxycycline group versus 0/48 (0%), and 6/22 (27.27%) in mild-moderate and severe COVID-19 patients, respectively in standard therapy group (p=0.052).
• The mean time to recovery was 6.34, 20.27, and 24.13 days in mild-moderate, severe, and critical COVID-19 patients, respectively in Ivermectin-Doxycycline group versus 13.66 and 24.25 days in mild-moderate and severe COVID-19 patients, respectively in standard therapy group (P<0.01).
• Ivermectin with doxycycline reduced time to recovery and the percentage of patients who progress to more advanced stage of disease. Ivermectin with doxycycline reduced mortality rate in severe patients from 22.72% to 0%; however, 18.2% of critically ill patients died with Ivermectin and doxycycline therapy. Taken together, the earlier administered Ivermectin with doxycycline, the higher rate of successful therapy.
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Population Results
Randomised, double-blind,
July 2020 (45 days)
Treatment arms (each arm:
• Arm1: Single dose ivermectin (200 mcg/Kg)
• Arm2: three low doses of ivermectin (200 mcg/Kg) on day 1, 3 and 5
• Arm3: single dose ivermectin (400 mcg/Kg)
• Arm 4: three high doses of ivermectin (400, 200, 200 mcg/Kg) on day 1, 3 and 5.
• Arm5: Iran health ministry SOC (hydroxychloroquine)
• Arm6: Placebo + SOC
180 mild to severe hospitalised patients with confirmed PCR and chest image tests. Average age: 56 years (45-67) and 50% were women.
Primary outcomes: chest image (CT scan) at hospital clearance, hospitalisation time fo duration of intervention, CRP and CBC at day 0 and 7 of intervention,
• Results showed significant changes between day 0 and day 5 of admission (Δ 0/5) in terms of ΔALC5/0, ΔPLT5/0, ΔESR5/0, ΔCRP5/0, duration of low O2 saturation, and duration of hospitalisation (CI = 95%).
• Reduction in mortality rate - ivermectin (0, 10, 0 and 3.3% for arms 1-4 respectively), vs. SOC + placebo + standard arms (16.7% and 20% respectively)
• Ivermectin decreased hospitalisation and low O2 saturating duration compared to the two untreated controls (P=0.006 and P=0.025 respectively).
• The lowest mortality rate (0%), hospitalisation duration (5days), and duration of low O2 saturatin (2days) was observed arm 3 with single dose of 400mcg/kg ivermectin.
• Risk of mortality in ivermectin group (3.3%, 95% CI 1.0%-8.5%) vs. control (18.3%, 95% CI 10.4%-30.1%)
Barcelona Institute for Global Health press release (19/01/2021). 2020-001474-29 (SAINT) Stromectol (Ivermectin) 3mg tablet single dose
Phase 2, Randomised Controlled Parallel Assignment Double blind trial. Spain. Ivermectin vs placebo
24 adult patients with confirmed COVID-19 and mild symptoms.
• Results show that that early administration of ivermectin can reduce viral loads and symptom duration in patients with mild COVID-19, which in turn could help reduce viral transmission.
• 7 days after treatment, no difference was observed in the percentage of PCR-positive patients (100% of patients were positive in both groups).
• The mean viral load in the ivermectin-treated group was lower (around 3x lower at 4 days and up to 18x lower at 7 days post-
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Population Results
treatment), although the difference was not statistically significant.
• Treated patients also showed a reduced duration of certain symptoms (of 50% for loss of smell and taste and of 30% for cough).
• All patients developed virus-specific IgG but, the mean level of antibodies in the treated group was lower than in the placebo group.
• There was no effect on duration of symptoms or makers associated with inflammation, which suggests ivermectin may act through mechanisms that do not involve an anti- inflammatory effect. Trial authors believe it could be interfering with viral entry in the cells.
medRxiv Ravikirti et al., 2021 CTRI/2020/08/027225 (link unavailable) Ivermectin tablet 12 mg
on day 1 and day 2 of
admission.
112 hospitalised adults
(≥18 years) admitted
placebo)
The primary outcome measure was a negative RT-PCR test for SARS-CoV-2 on day 6 of admission. The secondary outcome measures were symptom status on day 6, discharge status on day 10, admission to ICU, need for invasive mechanical ventilation and in-hospital mortality. There was no significant difference in the primary outcome -
negative RT-PCR status on day 6 between the two groups.
• 23.6% (n=13) in the intervention arm and 31.6 % (n=18) in the
placebo arm tested RT-PCR negative for SARS-CoV-2 on day 6
(RR 0.8, 95% CI 0.4 to 1.4, p=0.347).
There was no significant difference between the two groups in most of the secondary outcome measures:
• Asymptomatic by day 6: 83.6% (n=46) in the ivermectin arm vs. 89.5% (n=51) in the placebo arm (RR 0.9, 95% CI 0.8 to 1.1, p=0.363).
• Discharged by day 10: 80% (n=44) in ivermectin arm vs. 73.7% (n=42) in placebo arm (RR 1.2, 95% CI 0.7 to 1.9, p=0.428).
• Discharge by end of study: 100% ivermectin arm (n=55) vs. 93% (n=53) in the placebo arm (RR 1.1, 95% CI 1.0 to 1.2, p=0.019).
• Required ICU care: 9.1% (n=5) in ivermectin arm vs. 10.5% (n=6) in the placebo arm (RR 0.9, 95% CI 0.3 to 2.7, p=0.798).
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Population Results
• Need for invasive ventilation: 1.8% (n=1) in the ivermectin arm vs. 8.8% (n=5) in the placebo arm (RR 0.2, 95% CI 0 to 1.7, p=0.088).
• In-hospital mortality: no deaths in the ivermectin arm vs. 6.9% (n=4) in the placebo arm (RR 1.1, 95% CI 1.0 to 1.2, p=0.019).
Elsevier Ahmed et al., 2020 CTRI/2020/08/027225 (link unavailable) Ivermectin tablet, 12 mg once daily for 5 days
Randomised, double-blind, placebo-controlled trial. Bangladesh. Arms included:
• Ivermectin alone
• Ivermectin + doxycycline
were female.
Primary outcomes: Time required for virological clearance (a negative rRT-PCR result on nasopharyngeal swab), and remission of fever (≥37.5 °C) and cough within 7 days.
• Mean duration to viral clearance was 9.7 days (95% CI 7.8–11.8 days) for the ivermectin arm (p = 0.02), 11.5 days (95% CI 9.8– 13.2 days) for the ivermectin + doxycycline (p = 0.27) arm, and 12.7 days (95% CI 11.3–14.2 days) for the placebo group. Kaplan–Meier survival analysis revealed that the proportion of patients at risk of SARS-CoV-2 was reduced in the ivermectin group. Virological clearance in the ivermectin group was earlier compared to the placebo group on days 7 and 14 (hazard ratio (HR) 4.1, 95% CI 1.1–14.7 (P = 0.03) and HR 2.7, 95% CI 1.2– 6.0 (P = 0.02)). The trend was similar for the ivermectin + doxycycline group on days 7 and 14, but this was not statistically significant (HR 2.3, 95% CI 0.6–9.0 (P = 0.22) and HR 1.7, 95% CI 0.8–4.0 (P = 0.19)).
• Fever At enrolment, 82.6% (19/23) of patients in the placebo group, 73.9% (17/23) in the ivermectin + doxycycline group, and 77.3% (17/22) in the 5-day ivermectin group were recorded as having a fever, among whom 84.2% (16/19), 94.1% (16/17), and 100% (17/17), respectively, were afebrile on day 7, changes were not statistically significant for fever (p = 0.35 and p = 0.09), in the ivermectin + doxycycline and the ivermectin groups when compared with placebo.
• Cough Similarly, 65.2% (15/23) in the placebo group, 82.6% (19/23) in the ivermectin + doxycycline group, and 81.8% (18/22) in the ivermectin group had a cough on enrolment. On day 7, this dropped to 40% (9/15), 63.2% (7/19), and 61.1%
(7/18), respectively, for cough. Changes were not statistically
significant (p = 0.18 and p = 0.23), in the ivermectin +
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Population Results
doxycycline and the ivermectin groups when compared with placebo.
Secondary outcome: Failure to maintain an SpO2 >93% despite oxygenation and days on oxygen support, the duration of hospitalisation, and all-cause mortality.
• Mean duration of hospitalisation after treatment was 9.7 days (95% CI, 8.1–11.0 days) in the placebo group, 10.1 days (95% CI 8.5–11.8 days) in the ivermectin + doxycycline group, and 9.6 days (95% CI 7.7–11.7 days) in the ivermectin alone group (P = 0.93).
• There were no severe adverse drug events recorded in the study.
Prevention
Prospective, Observational, Cohort study. Argentina. Ivermectin + Carrageenan + PPE vs PPE alone 1,195 health professionals recruited of which 407 received no treatment and 788 self-administered ivermectin oral drops and an iota-carrageenan nasal spray five times per day for 14 days.
1,195 adults (18 years+) that have tested negative for COVID-19.
Primary outcome: Number of participants testing positive for COVID- 19 after inclusion in each arm
• COVID-19 infection in the control group (58%) vs 0% in the intervention arm (carrageenan plus ivermectin) This suggests the compound’s virucidal effects can protect patients against SARS-CoV-2 and serve as a sort of prophylaxis.
Shouman et al., 2020 NCT04422561 Trial registry result
Phase 2/3 open label RCT n=304 Egypt Intervention: ivermectin tablets, 40-60 kg (15mg/day)
Asymptomatic family close contact of confirmed COVID -19 patient.
Primary outcome: Development of Symptoms by day 14 7.4% vs. 58.4% All-cause mortality 0% vs. 0% Serious adverse events 0% vs. 0%
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Population Results
Treatment and Prevention
NCT04668469 Ivermectin tablet
assignment, triple blinded,
controlled trial. Egypt.
600 subjects; 400 symptomatic confirmed COVID-19 patients and 200 health care and household contacts distributed over 6 groups;
• Group 1: 100 patients with mild/moderate disease treated with 4- day course of Ivermectin + SOC
• Group 2: 100 patients with mild/moderate disease treated with hydroxychloroquine + SOC
• Group 3: 100 patients with severe disease treated with Ivermectin + SOC
• Group 4: 100 patients with severe disease treated with hydroxychloroquine + SOC
600 subjects; 400 symptomatic confirmed COVID-19 patients with mild, moderate and severe disease and 200 health care and household contacts
• Patients that received ivermectin had reduced mortality and disease progression rate.
o Mortality rate in mild/moderate disease: ivermectin (0%) vs. control (4%)
o Mortality rate in severe disease: ivermectin (2%) vs. control (20%)
o Disease progression rate in mild/moderate disease: ivermectin (1%) vs. control (22%)
o Disease progression rate in severe disease: ivermectin (4%) vs. control (30%) P=<0.001
• Ivermectin + SOC also increased clinical improvement. o Clinical improvement in mild/moderate disease:
ivermectin (99%) vs. control (74%) o Clinical improvement in in severe disease: ivermectin
(94%) vs. control (50%) P=<0.001
• Ivermectin + SOC reduced rt-PCR conversion days: o RT- PCR (days) mean ±S.D in mild/moderate disease:
ivermectin (5 ±1) vs. control (15 ±8) o RT- PCR (days) mean ±S.D in severe disease:
ivermectin (6 ±8) vs. control (18 ±8) P=<0.001 Ivermectin reduced the incidence of infection in health care and household contacts: ivermectin 2% vs. control (PPE) 10% when used as a prophylaxis. P=<0.05
Results show early addition of Ivermectin to SOC reduces mortality, rt-PCR conversion days, recovery time and hospital stay compared to hydroxychloroquine plus standard care. Early use of Ivermectin is also useful for prophylaxis and improving cytokine storm.
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Population Results
• Group 5: PPE + Ivermectin 0.4mg / kg
Group 6: PPE only. Both groups 5 and 6 were followed for two weeks.
Source: NICE Information Services literature search (04/03/2021)
Abbreviations: PCR, Polymerase Chain Reaction; BMI, Body Mass Index
C. Observational studies
Population Results
Retrospective study
Active group (AG): nitazoxanide, ivermectin, or hydroxychloroquine in selected cases, in association with azithromycin. Vitamin D, vitamin C, zinc, glucocorticoids and anticoagulants, when clinically recommended.
Active group (AG): mild-to-
moderate early stage COVID-19
AndroCoV Trial.
the Pre-AndroCoV Trial.
Control Group 2 (CG2): precise prediction of clinical outcomes, based on review of articles indexed in PubMed and MEDLINE and statements by official government agencies and specific medical societies.
• Compared to CG1 and CG2, AG showed a reduction of 31.5 to 36.5% in viral shedding (p < 0.0001), 70 to 85% and 70 to 73% in duration of COVID-19 clinical symptoms when including and not including anosmia and ageusia, respectively (p <0.0001 for both), and 100% in respiratory complications through the parameters of the Brescia COVID-19 Respiratory Scale (p < 0.0001).
• For every 1,000 confirmed cases for COVID-19, a minimum of 140 patients were prevented from hospitalisation (p < 0.0001), 50 from mechanical ventilation, and five deaths, when comparing to age-, sex- and comorbidity-matched non-treated patients with similar initial disease severity at the moment of diagnosis.
The study concluded that early pharmacological approaches
including azithromycin in combination with any of the options between nitazoxanide, ivermectin or optionally hydroxychloroquine should be considered for those diagnosed with COVID-19 presenting less than seven days of symptoms.
medRxiv Soto-Becerra et al. 2020 Ivermectin tablet
Retrospective cohort emulation
and high level hospitals from the
5683 adults aged 18-104 years,
(mean age 59.4 years)
Primary outcome was all-cause mortality rate
• 49 (15.3%) in hydroxychloroquine, 47 (24.5%) in
ivermectin, 325 (23.2%) in azithromycin, 165 (23.5%) in
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Population Results
01/April/2020–19/July/2020
5 treatment groups (HCQ alone, IVM alone, AZIT alone, HCQ+AZIT, and IVM+AZIT within 48 hours of admission) compared to standard of care (SOC)
azithromycin (n=692), ivermectin + azithromycin (n=358), SOC (n=2630)
hydroxychloroquine + azithromycin and 85 (23.5%) in
ivermectin + azithromycin.
higher all-cause death and/or ICU transfer hazard in the
weighted analysis (wHR = 1.58, 95% CI:1.11-2.25)
The study reported no beneficial effects of hydroxychloroquine, ivermectin, azithromycin. The hydroxychloroquine + azithromycin treatment seems to increase risk for all-cause death.
medRxiv Rajter 2020 (ICON study)
Ivermectin tablet
Retrospective cohort study Enrollment dates were March 15, 2020 through May 11, 2020. Florida. Ivermectin vs usual care Patients hospitalised at four Broward Health hospitals in South Florida with confirmed SARS-CoV- 2.
280 adults aged 18 years+
hospitalised with
and 107 were usual care were
reviewed.
reviewed
Primary endpoint, All-cause in-hospital mortality.
• Univariate analysis showed lower mortality in the ivermectin group (15.0%) versus control group (25.2%) OR 0.52, 95% CI 0.29-0.96, P=.03).
Secondary endpoints, subgroup mortality in patients with severe pulmonary involvement and extubation rates for patients requiring invasive ventilation.
• Mortality was lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8%) vs control (80.7%), OR 0.15, CI 0.05-0.47, P=.001)
no significant difference in successful extubation rates in the ivermectin group (36.1%) vs control (15.4%), OR 3.11 (0.88- 11.00), p=.07).
Research Square Chowdhury 2020
Observational study. Bangladesh. Ivermectin + Doxycycline vs Hydroxychloroquine + Azithromycin. Upazila Health & Family Planning Officer's Office
116 adults aged 16-80 years Non-hospitalised Mild to moderate degree of illness. Oxygen Saturation >94%, BMI<30 and no severe uncontrolled comorbid conditions.
Primary endpoint, Number of participants with "treatment success" determined by a negative PCR for COVID-19.
• Ivermectin + Doxycycline recovery to negative PCR rate was 100% (60/60). The mean recovery duration to negative PCR was 8.93 days (8 to 13 days).
• Hydroxychloroquine + Azithromycin recovery to negative PCR rate was 96.36% (54/56). The mean duration of recovery to negative PCR was 9.33 days (5-15 days).
• The difference between Group A and Group B recovery to negative PCR duration is not statistically significant in unpaired t-test, P = 0.2314
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Population Results
• The unpaired t-test between the recovery duration of both group male and both group female individually were not significant P = 0.18 and 0.69, respectively.
Secondary endpoints, Number of participants with "adverse effects" determined by the existence of the pharmacological side effects of the particular drug during treatment.
• Ivermectin + Doxycycline new symptoms that may be attributed to drug adverse effect or progression of COVID-19 disease included lethargy in 14(23.3%), nausea in 11(18.3%), and occasional vertigo in 7(11.66%) of patients.
Hydroxychloroquine + Azithromycin new symptoms that may be attributed to drug adverse effect or progression of COVID- 19 disease included 13(23.21%) with mild blurred vision and headache; 22 (39.2%) with increased lethargy and dizziness, 10 (17.85%) with occasional, mild palpitation, and 9 (16.07%) with nausea and vomiting.
Source: NICE Information Services literature search (11.08.2020) Note: Published evidence has been excluded where they are case studies.
Abbreviations: PCR, polymerase chain reaction
Appendix 2: Ongoing trials
A. Completed (no results)
Primary completion date
Phase 2-3 Randomised Single Blinded Parallel Assignment
Iran
Unknown (recruitment complete).
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Ivermectin (200– 150μg/kg on day 1) and chloroquine and lopinavir / ritonavir
Ivermectin and chloroquine and lopinavir / ritonavir vs chloroquine and lopinavir / ritonavir
• Pneumonic manifestations of the virus, shown by:
• CT scans of the lungs
• O2 Saturation of ≤93%
7 days, determined by the percentage of discharged COVID-19 patients.
IRCT20200408046987N1 Ivermectin (200 mcg/kg once daily)
Chistasazan notash fartak
Phase 3 Randomised Double blinded Parallel Assignment Ivermectin once daily and standard of care vs ivermectin on days:1,2,5 and standard of care vs standard of care and placebo
Iran • Adult (20-64 years) with a temperature (oral) ≥38.0°C
• Adult (65-80 years) with a temperature (oral) ≥38.0°C at the first visit or in the 6 hours prior if antipyretics taken
• Hospitalised
• Confirmed COVID-19
• Patients with 2 or more of the following symptoms (moderate to severe in intensity):
• Cough
• Enrollment Number: 100
Chest image (CT scan) at hospital clearance Hospitalisation time by the end of intervention CBC and CRP before the intervention and 7 days after intervention according to sampling and lab test
Unknown. (recruitment complete).
Laboratorio Elea Phoenix S.A.
Phase 2 Randomised Parallel Assignment Open Label Ivermectin and standard of care
Argentina • Adult (18-69 years)
• Confirmed COVID-19 (positive PCR)
• Hospitalised patients with symptom onset within 5 days of enrollment.
• No comorbidities/high risk
Number of patients in whom the SARS-CoV-2 viral load decreases after Ivermectin
29/09/2020
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vs standard of care • Women of childbearing age must have negative pregnancy test and use contraceptive throughout study.
Prevention
Zagazig University
Egypt • Adult (16-70 years)
Appearance of symptoms (fever, cough, sore throat, myalgia, diarrhea, shortness of breath) within 14 days after enrollment
01/07/2020
National University Hospital, Singapore
Singapore • Adult (21-60 years)
• No history of cardiac or neurological diseases, retinal diseases, insulin dependent diabetes, chronic alcoholism, renal or hepatic dysfunction, glucose-6- phosphate dehydrogenase deficiency, medication related anaemia, thyroid disorder, allergies with systemic presentation
Incidence of acute respiratory illness in treatment arms. Acute respiratory illness is defined by acute onset with any key respiratory symptoms including cough, shortness of breath, sore throat, runny nose and change in smell.
31/08/2020
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Source: National Institute for Health Research Innovation Observatory (scan 15/10/2020)
Abbreviations: PCR, Polymerase Chain Reaction; BMI, Body Mass Index
*PCD (Primary Completion Date) defined on clinicaltrials.gov as the date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. The "estimated" primary completion date is the date that the researchers think will be the primary completion date for the study.
B. Recruiting
Treatment
NCT04374019 Ivermectin tablet days 1-2: Weight < 75kg: 12 mg daily Weight > 75kg: 15 mg daily
Susanne Arnold Phase 2, Randomised Parallel Assignment, Open Label Ivermectin vs hydroxychloroquine and azithromycin vs camostat mesylate vs dietary supplement (artemesia annua)
United States
• Adult (18-99)
• COVID-19 confirmed by: - Lab results within past 7 days - symptoms - physical examination signs
• Adequate organ and marrow function measured within the last 6 months
• >45kg
• Not pregnant/ breast-feeding
• Subjects must 1+ of the following high-risk features for clinical deterioration:
- Hypertension - Diabetes Mellitus - Moderate to severe COPD,
emphysema, cystic fibrosis, or asthma
- Cancer treated with immunosuppressant within 1 year from enrollment
Proportion of patients experiencing clinical deterioration. Defined as a less than a 2-point change from the initial COVID 7- Point Ordinal Outcomes Scale within 14 days from the study start. This scale ranges from 1-7. Lower scores indicate worse outcomes (death); higher scores indicate fewer symptoms
01/05/2021
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Sponsor Design
Location Population
Primary endpoints
Estimated PCD*
- Sickle cell or thalassemia - Age ≥50 - BMI ≥30 - Living in nursing home or long-
term facility - Underlying serious heart
condition - Immunocompromised
Enrollment Number: 240
and better outcomes.
Fundació Assistencial Mútua Terrassa
Spain Both sub studies:
• Adult (18-64 years)
• Negative pregnancy test in women of childbearing age and use of contraception during the study
• Adequate liver and renal (GFR >30 mL/min/1.73 m2) function
• No coagulation disorders, neurological or mental impairment
• No participation in any other study in the previous 30 days
Sub-study 1 only:
• Symptomatic (respiratory) patients
• Clinical condition of less than 5 days of evolution.
• Not hospitalised (mild infection)
• No respiratory distress
Sub-study 1: Virological clearence at 3, 6, 9 and 12 days after starting treatment with Ivermectin. Sub-study 2: Incidence of secondary cases diagnosed by molecular biology and serology on the 7th, 14th, 21st day after starting prophylaxis with Ivermectin and with placebo.
Unknown, Registration date: 08/05/2020
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• Kirby index:(PaO2) /(FIO2)) >300mmHg.
Sub-study 2 only:
• Contacts of symptomatic (respiratory) patients with a positive PCR for COVID-19 and diagnosis within 5 days of evolution.
NCT04405843 Ivermectin tablet 300 micrograms / kg, once daily for 5 days
Centro de Estudios en Infectogía Pediatrica
Phase 2/3, Randomised Controlled Parallel Assignment, Double Blind Ivermectin vs placebo
Colombia • Adult (18 years +)
• Mild disease
• Not pregnant/breastfeeding
• Adequate liver function Enrollment Number: 400
Time until deterioration of 2 or more points in an ordinal 7 points scale within 21 days after enrollment.
01/11/2020
NCT04399746 IvAzCol Combination Ivermectin (form not stated) (6mg once daily in day 0,1,7 and 8) and Azithromycin and Cholecalciferol
Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado
Non-Randomised Parallel Assignment, Open Label Ivermectin and azithromycin and cholecalciferol vs control (no intervention)
Mexico • Aged 18-90 years
• Fever (>38 °C)
Viral clearance within 14 days determined by testing for virus at day 1 and 14 from beginning of trial drug started.
20/05/2020 (still recruiting according to the registry)
NCT04425707 Ivermectin (form and dose not stated)
Ministry of Health and Population, Egypt
Phase (unknown), Randomised Parallel Assignment, Open Label
Egypt • Adult (18 years+)
• Asymptomatic mild and moderate cases proven to be infected by COVID 19 by viral RNA swap
To evaluate the role of Ivermectin as a line of treatment for
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Sponsor Design
Location Population
Primary endpoints
Estimated PCD*
Ivermectin and standard care vs Ivermectin alone vs standard care alone
• Not pregnant/breastfeeding
NCT04392713 Ivermectin 6 mg tablet (2 tablets) Standard care includes chloroquine
Combined Military Hospital, Pakistan
Pakistan • Aged 15-65 years
• No malignant diseases, diabetes mellitus or Cytokine Release Storm
Negative PCR within 144 hours. PCR will be done at 48, 96 and 144 hours.
01/07/2020
NCT04407130 Combination Ivera® (Ivermectin) tablet (200 mcg/kg (12 mg tablet) single dose) and doxycycline and placebo Ivermectin (200 mcg/kg (12 mg tablet) once daily from day 1 to 5) and Placebo
International Centre for Diarrhoeal Disease Research, Bangladesh
Phase 2, Randomised Parallel Assignment Double Blind Ivermectin and doxycycline and placebo vs ivermectin and placebo
Bangladesh • Adult (40-65 years)
- Temp ≥37.5 C - Cough - Sore throat - SpO2 >94%
• Duration of illness ≤ 7 days
• No oxygen support
Presence of virus will be negative on Day 7 detected by PCR Body temperature will be between 36.1 to 37.2 C by day 7 detected by Infrared thermometer Remission of cough: No signs of cough showing respiratory rate within 12-20/min, on day 7
01/07/2020 (still enrolling by invitation according to the registry)
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Sponsor Design
Location Population
Primary endpoints
Estimated PCD*
NCT04373824 Combination: Ivermectin (form not stated) (200 to 400 mcg/kg on day 1 and day 2) and standard treatment
Max Healthcare Insititute Limited
India • Adult (18-75 years)
Effect of Ivermectin on eradication of virus within 3 months, determined by testing for virus at 1, 3 & 5 days from beginning of trial.
25/07/2020
NCT04445311 Ivermectin (form not stated) 3 successive days of treatment started within 48 hours of symptoms
Zagazig University
Phase 2/3, Randomised Parallel Assignment, Open Label Standard of care vs Ivermectin and standard of care
Egypt • Adult (18-

Briefing: Ivermectin (generic) C19-026

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Briefing: Ivermectin (generic) C19-026