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Ivermectin for COVID-19: real-time meta analysis of 60 studies
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Meta analysis using the most serious outcome reported shows 74% and 85% improvement for early treatment and prophylaxis (RR 0.26 [0.16-0.43] and 0.15 [0.08-0.25]), with similar results after exclusion based sensitivity analysis, restriction to peer-reviewed studies, and restriction to Randomized Controlled Trials.
64% and 96% lower mortality is observed for early treatment and prophylaxis (RR 0.36 [0.15-0.85] and 0.04 [0.00-0.59]). Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 26 studies show statistically significant improvements in isolation.
Studies Prophylaxis Early treatment Late treatment PatientsAuthors
All studies 60 85% [75‑92%] 74% [57‑84%] 43% [26‑56%] 21,838 574
With exclusions 50 88% [75‑94%] 76% [66‑83%] 50% [28‑65%] 17,437 513
Peer-reviewed 39 88% [70‑95%] 75% [59‑84%] 43% [21‑59%] 11,593 408
Randomized Controlled Trials 30 84% [25‑96%] 67% [54‑76%] 30% [2‑50%] 5,206 358
Mortality results 23 96% [41‑100%] 64% [15‑85%] 59% [35‑74%] 10,797 236
Percentage improvement with ivermectin treatment
The probability that an ineffective treatment generated results as positive as the 60 studies to date is estimated to be 1 in 193 billion (p = 0.0000000000052).
Heterogeneity arises from many factors including treatment delay, population, effect measured, variants, and regimens. The consistency of positive results is remarkable. Heterogeneity is low in specific cases, for example early treatment mortality.
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 30% of ivermectin studies show zero events in the treatment arm.
Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. All practical, effective, and safe means should be used. Those denying the efficacy of treatments share responsibility for the increased risk of COVID-19 becoming endemic; and the increased mortality, morbidity, and collateral damage.
Administration with food, often not specified, may significantly increase plasma and tissue concentration.
The evidence base is much larger and has much lower conflict of interest than typically used to approve drugs.
All data to reproduce this paper and sources are in the appendix. See [Bryant, Hariyanto, Hill, Kory, Lawrie, Nardelli] for other meta analyses, all with similar results confirming effectiveness.
00.250.50.7511.251.51.752+Kory et al.69%0.31 [0.20-0.47]Improvement, RR [CI]Hill et al.75%0.25 [0.12-0.52]Bryant et al.62%0.38 [0.19-0.73]Lawrie et al.83%0.17 [0.08-0.35]Nardelli et al.79%0.21 [0.11-0.36]Hariyanto et al.69%0.31 [0.15-0.62]WHO (OR)81%0.19 [0.09-0.36]ivmmeta67%0.33 [0.21-0.51]Ivermectin meta analysis mortality resultsivmmeta.com 7/28/21Lower RiskIncreased Risk
Evidence base used for other COVID-19 approvals
MedicationStudiesPatientsImprovement
Budesonide (UK)11,77917%
Remdesivir (USA)11,06331%
Casiri/imdevimab (USA)179966%
Ivermectin evidence6021,814 70% [61‑76%]
    
  
A
00.250.50.7511.251.51.752+Chowdhury (RCT)81%0.19 [0.01-3.96]14mghosp.0/602/56OT​1 CT​2Improvement, RR [CI]Dose (4d)TreatmentControlEspitia-Hernandez97%0.03 [0.01-0.11]12mgviral+0/287/7CT​2Carvallo88%0.12 [0.01-1.06]36mgdeath1/333/12CT​2Mahmud (DB RCT)86%0.14 [0.01-2.75]12mgdeath0/1833/183CT​2Szente Fonseca-14%1.14 [0.75-1.66]24mghosp.340377Cadegiani78%0.22 [0.01-4.48]42mgdeath0/1102/137CT​2Ahmed (DB RCT)85%0.15 [0.01-2.70]48mgsymptoms0/173/19Chaccour (DB RCT)53%0.47 [0.19-1.16]28mgsymp. prob.1212Afsar92%0.08 [0.00-1.32]48mgsymptoms0/377/53Babalola (DB RCT)64%0.36 [0.10-1.27]24mgviral+4020OT​1Ravikirti (DB RCT)89%0.11 [0.01-2.05]24mgdeath0/554/57Bukhari (RCT)82%0.18 [0.07-0.46]12mgviral+4/4125/45Samaha (RCT)86%0.14 [0.01-2.70]12mghosp.0/503/50Mohan (DB RCT)62%0.38 [0.08-1.75]28mgno recov.2/406/45Biber (DB RCT)70%0.30 [0.03-2.76]36mghosp.1/473/42Elalfy87%0.13 [0.06-0.27]36mgviral+7/6244/51CT​2López-Me.. (DB RCT)67%0.33 [0.01-8.11]84mgdeath0/2001/198Roy6%0.94 [0.52-1.93]n/arecov. time1415CT​2Chahla (CLUS. RCT)87%0.13 [0.03-0.54]24mgno disch.2/11020/144Mourya89%0.11 [0.05-0.25]48mgviral+5/5047/50Loue (QR)70%0.30 [0.04-2.20]14mgdeath1/105/15Merino (QR)74%0.26 [0.11-0.61]24mghosp.population-based cohortFaisal (RCT)68%0.32 [0.14-0.72]48mgno recov.6/5019/50Aref (RCT)63%0.37 [0.22-0.62]recov. time5757Krolewiecki (RCT)-152%2.52 [0.11-58.1]168mgventilation1/270/14Vallejos (DB RCT)-33%1.33 [0.30-5.72]24mgdeath4/2503/251Tau​2 = 0.95; I​2 = 81.6%Early treatment74%0.26 [0.16-0.43]34/1,923207/1,96074% improvementShouman (RCT)91%0.09 [0.03-0.23]36mgsymp. case15/20359/101Improvement, RR [CI]Dose (1m)TreatmentControlCarvallo96%0.04 [0.00-0.63]14mgcases0/13111/98CT​2Behera54%0.46 [0.29-0.71]42mgcases41/117145/255Carvallo100%0.00 [0.00-0.02]48mgcases0/788237/407CT​2Hellwig (ECO.)78%0.22 [0.05-0.89]14mgcasesecologicalBernigaud99%0.01 [0.00-0.10]84mgdeath0/69150/3,062Alam91%0.09 [0.04-0.25]12mgcases4/5844/60Vallejos73%0.27 [0.15-0.48]48mgcases13/38961/486MD​3Chahla (RCT)95%0.05 [0.00-0.80]48mgm/s case0/11710/117CT​2Behera83%0.17 [0.12-0.23]42mgcases45/2,199133/1,147Tanioka (ECO.)88%0.12 [0.03-0.51]14mgdeathecologicalSeet (CLUS. RCT)50%0.50 [0.33-0.76]12mgsevere case32/61764/619OT​1Morgenstern (PSM)80%0.20 [0.01-4.15]56mghosp.0/2712/271Tau​2 = 0.60; I​2 = 85.0%Prophylaxis85%0.15 [0.08-0.25]150/4,959916/6,62385% improvementAll studies80%0.20 [0.14-0.30]184/6,8821,123/8,58380% improvementIvermectin COVID-19 early treatment and prophylaxis studiesivmmeta.com 7/28/211 OT: ivermectin vs. other treatment2 CT: study uses combined treatment3 MD: minimal detail available currentlyTau​2 = 0.91; I​2 = 89.0%; Z = 7.93 (p < 0.0001)Effect extraction pre-specified, see appendixLower RiskIncreased Risk
    
  
B
00.250.50.7511.251.51.752+All studiesEarly treatmentmin, Q1, median, Q3, maxLower RiskIncreased Riskivmmeta.com 7/28/21
    
  
C
100+ 75 50 25 25 50 75 100 Chowdhuryhosp., p=0.23Espitia-Hernandezviral+, p<0.0001Carvallodeath, p=0.05Mahmuddeath, p=0.25Szente Fonsecahosp., p=0.45Cadegianideath, p=0.50Ahmedsymptoms, p=0.09Chaccoursymp. prob., p<0.05Afsarsymptoms, p=0.04Babalolaviral+, p=0.11Ravikirtideath, p=0.12Bukhariviral+, p<0.0001Samahahosp., p=0.24Mohanno recov., p=0.27Biberhosp., p=0.34Elalfyviral+, p<0.0001López-Medinadeath, p=0.50Royrecov. time, p=0.87Chahlano disch., p=0.004Mouryaviral+, p<0.0001Louedeath, p=0.34Merinohosp., p<0.001Faisalno recov., p=0.005Arefrecov. time, p=0.0001Krolewieckiventilation, p=1.00Vallejosdeath, p=0.70Early treatment% Lower Risk% Increased Riskivmmeta.com 7/28/21Probability results fromineffective treatmentJan 8 p<0.011 in 100Feb 1 p<0.0011 in 1 thousandMar 11 p<0.00011 in 10 thousand
    
  
D
100+ 75 50 25 25 50 75 100 Gorial, death, p=1.00Chowdhury, hosp., p=0.23Espitia-Hernandez, viral+, p<0.0001Shouman, symp. case, p<0.001Kishoria, no disch., p=1.00Podder, recov. time, p=0.34Carvallo, death, p=0.05Khan, death, p<0.05Chachar, no recov., p=0.50Soto-Becerra, death, p=0.01Mahmud, death, p=0.25Rajter, death, p=0.04Carvallo, cases, p<0.0001Hashim, death, p=0.03Szente Fonseca, hosp., p=0.45Behera, cases, p<0.0001Cadegiani, death, p=0.50Camprubí, ventilation, p=0.67Spoorthi, recov. time, p=0.03Carvallo, cases, p<0.0001Budhiraja, death, p=0.04Niaee, death, p=0.001Hellwig, cases, p<0.02Bernigaud, death, p=0.08Ahmed, symptoms, p=0.09Chaccour, symp. prob., p<0.05Afsar, symptoms, p=0.04Alam, cases, p<0.0001Vallejos, cases, p<0.0001Babalola, viral+, p=0.11Ravikirti, death, p=0.12Chahla, m/s case, p=0.002Okumuş, death, p=0.55Bukhari, viral+, p<0.0001Samaha, hosp., p=0.24Shahbaznejad, death, p=1.00Mohan, no recov., p=0.27Lima-Morales, death, p<0.001Biber, hosp., p=0.34Behera, cases, p<0.001Elalfy, viral+, p<0.0001Gonzalez, death, p=1.00López-Medina, death, p=0.50Pott-Junior, ventilation, p=0.25Roy, recov. time, p=0.87Huvemek, no improv., p=0.28Tanioka, death, p=0.002Chahla, no disch., p=0.004Mourya, viral+, p<0.0001Seet, severe case, p=0.01Morgenstern, hosp., p=0.50Loue, death, p=0.34Ahsan, death, p=0.03Merino, hosp., p<0.001Faisal, no recov., p=0.005Abd-Elsalam, death, p=0.70Aref, recov. time, p=0.0001Krolewiecki, ventilation, p=1.00Vallejos, death, p=0.70Hazan, death, p=0.04All studies% Lower Risk% Increased Riskivmmeta.com 7/28/21Probability results fromineffective treatmentOct 8 p<0.011 in 100Nov 23 p<0.00011 in 10 thousandDec 1 p<0.000011 in 100 thousandDec 19 p<0.0000011 in 1 millionFeb 1 p<0.00000011 in 10 millionMar 81 in 1 billion
Figure 1. A. Random effects meta-analysis excluding late treatment. This plot shows pooled effects, analysis for individual outcomes is below, and more details on pooled effects can be found in the heterogeneity section. Effect extraction is pre-specified, using the most serious outcome reported. Simplified dosages are shown for comparison, these are the total dose in the first four days for treatment, and the monthly dose for prophylaxis, for a 70kg person. For details of effect extraction and full dosage information see the appendix. B. Scatter plot showing the distribution of effects reported in early treatment studies and in all studies. C and D. Chronological history of all reported effects, with the probability that the observed frequency of positive results occurred due to random chance from an ineffective treatment.
Introduction
We analyze all significant studies concerning the use of ivermectin for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for mortality results, for COVID-19 case results, for viral clearance results, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
We also perform a simple analysis of the distribution of study effects. If treatment was not effective, the observed effects would be randomly distributed (or more likely to be negative if treatment is harmful). We can compute the probability that the observed percentage of positive results (or higher) could occur due to chance with an ineffective treatment (the probability of >= k heads in n coin tosses, or the one-sided sign test / binomial test). Analysis of publication bias is important and adjustments may be needed if there is a bias toward publishing positive results.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Results
Figure 3, 4, and 5 show results by treatment stage. Figure 6, 7, 8, 9, 10, 11, and 12 show forest plots for a random effects meta-analysis of all studies with pooled effects, and for studies reporting mortality results, ICU admission, mechanical ventilation, hospitalization, COVID-19 cases, and viral clearance results only. Figure 13 shows results for peer reviewed trials only. Table 1 summarizes the results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Probability of an equal or greater percentage of positive results from an ineffective treatmentRandom effects meta-analysis results
Early treatment 23 26 88.5% 0.000044 4.4e-05
1 in 23 thousand
74% improvement
RR 0.26 [0.16‑0.43] p < 0.0001
Late treatment 19 21 90.5% 0.00011 0.00011
1 in 9 thousand
43% improvement
RR 0.57 [0.44‑0.74] p < 0.0001
Prophylaxis 13 13 100% 0.00012 0.00012
1 in 8 thousand
85% improvement
RR 0.15 [0.08‑0.25] p < 0.0001
All studies 55 60 91.7% 0.0000000000052 5.2e-12
1 in 193 billion
70% improvement
RR 0.30 [0.24‑0.39] p < 0.0001
Table 1. Results by treatment stage.
    
  
00.250.50.7511.251.51.752+All studiesLate treatmentEarly treatmentProphylaxismin, Q1, median, Q3, maxLower RiskIncreased Riskivmmeta.com 7/28/21
Figure 3. Results by treatment stage.
    
  
100+ 75 50 25 25 50 75 100 Chowdhuryhosp., p=0.23Espitia-Hernandezviral+, p<0.0001Carvallodeath, p=0.05Mahmuddeath, p=0.25Szente Fonsecahosp., p=0.45Cadegianideath, p=0.50Ahmedsymptoms, p=0.09Chaccoursymp. prob., p<0.05Afsarsymptoms, p=0.04Babalolaviral+, p=0.11Ravikirtideath, p=0.12Bukhariviral+, p<0.0001Samahahosp., p=0.24Mohanno recov., p=0.27Biberhosp., p=0.34Elalfyviral+, p<0.0001López-Medinadeath, p=0.50Royrecov. time, p=0.87Chahlano disch., p=0.004Mouryaviral+, p<0.0001Louedeath, p=0.34Merinohosp., p<0.001Faisalno recov., p=0.005Arefrecov. time, p=0.0001Krolewieckiventilation, p=1.00Vallejosdeath, p=0.70Early treatment% Lower Risk% Increased Riskivmmeta.com 7/28/21Probability results fromineffective treatmentJan 8 p<0.011 in 100Feb 1 p<0.0011 in 1 thousandMar 11 p<0.00011 in 10 thousand
    
  
100+ 75 50 25 25 50 75 100 Gorialdeath, p=1.00Kishoriano disch., p=1.00Podderrecov. time, p=0.34Khandeath, p<0.05Chacharno recov., p=0.50Soto-Becerradeath, p=0.01Rajterdeath, p=0.04Hashimdeath, p=0.03Camprubíventilation, p=0.67Spoorthirecov. time, p=0.03Budhirajadeath, p=0.04Niaeedeath, p=0.001Okumuşdeath, p=0.55Shahbaznejaddeath, p=1.00Lima-Moralesdeath, p<0.001Gonzalezdeath, p=1.00Pott-Juniorventilation, p=0.25Huvemekno improv., p=0.28Ahsandeath, p=0.03Abd-Elsalamdeath, p=0.70Hazandeath, p=0.04Late treatment% Lower Risk% Increased Riskivmmeta.com 7/28/21Probability results fromineffective treatmentOct 25 p<0.051 in 20Nov 17 p<0.011 in 100Mar 24 p<0.0011 in 1 thousand
Figure 4. Chronological history of early and late treatment results, with the probability that the observed frequency of positive results occurred due to random chance from an ineffective treatment.
100+ 75 50 25 25 50 75 100 Shoumansymp. case, p<0.001Carvallocases, p<0.0001Beheracases, p<0.0001Carvallocases, p<0.0001Hellwigcases, p<0.02Bernigauddeath, p=0.08Alamcases, p<0.0001Vallejoscases, p<0.0001Chahlam/s case, p=0.002Beheracases, p<0.001Taniokadeath, p=0.002Seetsevere case, p=0.01Morgensternhosp., p=0.50Prophylaxis% Lower Risk% Increased Riskivmmeta.com 7/28/21Probability results fromineffective treatmentNov 27 p<0.051 in 20Dec 14 p<0.011 in 100Feb 14 p<0.0011 in 1 thousand
Figure 5. Chronological history of prophylaxis results.
    
  
00.250.50.7511.251.51.752+Chowdhury (RCT)81%0.19 [0.01-3.96]14mghosp.0/602/56OT​1 CT​2Improvement, RR [CI]Dose (4d)TreatmentControlEspitia-Hernandez97%0.03 [0.01-0.11]12mgviral+0/287/7CT​2Carvallo88%0.12 [0.01-1.06]36mgdeath1/333/12CT​2Mahmud (DB RCT)86%0.14 [0.01-2.75]12mgdeath0/1833/183CT​2Szente Fonseca-14%1.14 [0.75-1.66]24mghosp.340377Cadegiani78%0.22 [0.01-4.48]42mgdeath0/1102/137CT​2Ahmed (DB RCT)85%0.15 [0.01-2.70]48mgsymptoms0/173/19Chaccour (DB RCT)53%0.47 [0.19-1.16]28mgsymp. prob.1212Afsar92%0.08 [0.00-1.32]48mgsymptoms0/377/53Babalola (DB RCT)64%0.36 [0.10-1.27]24mgviral+4020OT​1Ravikirti (DB RCT)89%0.11 [0.01-2.05]24mgdeath0/554/57Bukhari (RCT)82%0.18 [0.07-0.46]12mgviral+4/4125/45Samaha (RCT)86%0.14 [0.01-2.70]12mghosp.0/503/50Mohan (DB RCT)62%0.38 [0.08-1.75]28mgno recov.2/406/45Biber (DB RCT)70%0.30 [0.03-2.76]36mghosp.1/473/42Elalfy87%0.13 [0.06-0.27]36mgviral+7/6244/51CT​2López-Me.. (DB RCT)67%0.33 [0.01-8.11]84mgdeath0/2001/198Roy6%0.94 [0.52-1.93]n/arecov. time1415CT​2Chahla (CLUS. RCT)87%0.13 [0.03-0.54]24mgno disch.2/11020/144Mourya89%0.11 [0.05-0.25]48mgviral+5/5047/50Loue (QR)70%0.30 [0.04-2.20]14mgdeath1/105/15Merino (QR)74%0.26 [0.11-0.61]24mghosp.population-based cohortFaisal (RCT)68%0.32 [0.14-0.72]48mgno recov.6/5019/50Aref (RCT)63%0.37 [0.22-0.62]recov. time5757Krolewiecki (RCT)-152%2.52 [0.11-58.1]168mgventilation1/270/14Vallejos (DB RCT)-33%1.33 [0.30-5.72]24mgdeath4/2503/251Tau​2 = 0.95; I​2 = 81.6%Early treatment74%0.26 [0.16-0.43]34/1,923207/1,96074% improvementGorial71%0.29 [0.01-5.76]14mgdeath0/162/71Improvement, RR [CI]Dose (4d)TreatmentControlKishoria (RCT)-8%1.08 [0.57-2.02]12mgno disch.11/197/13Podder (RCT)16%0.84 [0.55-1.12]14mgrecov. time3230Khan87%0.13 [0.02-1.01]12mgdeath1/1159/133Chachar (RCT)10%0.90 [0.44-1.83]36mgno recov.9/2510/25Soto-Becerra17%0.83 [0.71-0.97]14mgdeath92/2031,438/2,630Rajter (PSM)46%0.54 [0.27-0.99]14mgdeath13/9824/98Hashim (SB RCT)92%0.08 [0.00-1.44]28mgdeath0/596/70CT​2Camprubí40%0.60 [0.18-2.01]14mgventilation3/135/13Spoorthi21%0.79 [0.62-1.01]n/arecov. time5050CT​2Budhiraja99%0.01 [0.00-0.15]n/adeath0/34103/942Niaee (DB RCT)82%0.18 [0.06-0.55]28mgdeath4/12011/60Okumuş (DB RCT)33%0.67 [0.27-1.64]56mgdeath6/309/30Shahbazn.. (DB RCT)-197%2.97 [0.13-70.5]14mgdeath1/350/34Lima-Morales78%0.22 [0.12-0.41]12mgdeath15/48152/287CT​2Gonzalez (DB RCT)14%0.86 [0.29-2.56]12mgdeath5/366/37Pott-Junior (RCT)85%0.15 [0.01-1.93]14mgventilation1/271/4Huvemek (DB RCT)32%0.68 [0.38-1.23]84mgno improv.13/5019/50Ahsan50%0.50 [0.28-0.90]21mgdeath17/11017/55CT​2Abd-Elsalam (RCT)25%0.75 [0.17-3.06]36mgdeath3/824/82Hazan86%0.14 [0.01-2.19]24mgdeath0/24syntheticCT​2 SC​4Tau​2 = 0.14; I​2 = 59.9%Late treatment43%0.57 [0.44-0.74]194/1,6591,723/4,71443% improvementShouman (RCT)91%0.09 [0.03-0.23]36mgsymp. case15/20359/101Improvement, RR [CI]Dose (1m)TreatmentControlCarvallo96%0.04 [0.00-0.63]14mgcases0/13111/98CT​2Behera54%0.46 [0.29-0.71]42mgcases41/117145/255Carvallo100%0.00 [0.00-0.02]48mgcases0/788237/407CT​2Hellwig (ECO.)78%0.22 [0.05-0.89]14mgcasesecologicalBernigaud99%0.01 [0.00-0.10]84mg