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Briefing: Ivermectin (generic) C19-026

Oct 03, 2021

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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
NEW
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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:…