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Ivermectin is effective for COVID-19: real-time meta analysis of 32 studies
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100% of the 32 studies to date report positive effects. Early treatment is more successful, with an estimated reduction of 85% in the effect measured using a random effects meta-analysis, RR 0.15 [0.06-0.37]. Prophylactic use also shows high effectiveness.
100% of the 14 Randomized Controlled Trials (RCTs) report positive effects, with an estimated reduction of 73%, RR 0.27 [0.15-0.51].
The probability that an ineffective treatment generated results as positive as the 32 studies to date is estimated to be 1 in 4 billion (p = 0.00000000023).
Early treatment 85% improvement RR 0.15 [0.06-0.37]
Late treatment 46% improvement RR 0.54 [0.39-0.75]
Prophylaxis 90% improvement RR 0.10 [0.04-0.23]
Total32 studies218 authors10,033 patients
RCT14 studies105 authors2,225 patients
A
00.250.50.7511.251.51.752+Espitia-Hernandez0.03[0.01-0.11]12mgviral-35RRCIDoseNCarvallo0.12[0.01-1.06]36mgdeath45Cadegiani0.22[0.01-4.48]28mgdeath247Ahmed (RCT)0.15[0.01-2.70]24mgsymptoms36Chaccour (RCT)0.44[0.16-1.17]28mgsymptoms24Afsar0.08[0.00-1.32]24mgsymptoms90Babalola (RCT)0.36[0.10-1.27]12mgviral-60Kirti (RCT)0.11[0.01-2.05]24mgdeath112Tau​2 = 0.58; I​2 = 39.2%Early0.15[0.06-0.37]649 patients85% improvementShouman (RCT)0.09[0.03-0.23]18mgsymp. case304Carvallo0.04[0.00-0.63]2mgcase229Behera0.50[0.31-0.73]21mgcase372Elgazzar (RCT)0.20[0.04-0.89]28mgcase200Carvallo0.00[0.00-0.02]12mgcase1,195Hellwig0.22[0.05-0.89]14mgcaseBernigaud0.01[0.00-0.10]28mgdeath138Alam0.09[0.04-0.24]12mgcase118Vallejos0.21[0.09-0.50]12mgcase873NCT04701710 (RCT)0.05[0.00-0.89]12mgcase234Tau​2 = 1.28; I​2 = 86.5%Prophylaxis0.10[0.04-0.23]3,663 patients90% improvementAll studies0.12[0.06-0.22]4,312 patients88% improvementIvermectin COVID-19 early treatment and prophylaxis studiesivmmeta.com 1/16/21Tau​2 = 1.08; I​2 = 78.7%; Z = 6.62 (p < 0.0001)Lower RiskIncreased Risk
B
00.250.50.7511.251.51.752+All studiesEarly treatmentmin, Q1, median, Q3, maxLower RiskIncreased Riskivmmeta.com 1/16/21
C
100+ 75 50 25 25 50 75 100 Espitia-Hernandezviral+, p<0.0001Carvallodeath, p=0.05Cadegianideath, p=0.50Ahmedsymptoms, p=0.09Chaccoursymptoms, p<0.05Afsarsymptoms, p=0.04Babalolaviral+, p=0.11Kirtideath, p=0.12Early treatment% Lower Risk% Increased Riskivmmeta.com 1/16/21Probability results fromineffective treatmentJan 6 p<0.011 in 100
D
100+ 75 50 25 25 50 75 100 Gorialdeath, p=1.00Espitia-Hernandezviral+, p<0.0001Shoumansymp. case, p<0.001Podderrecov. time, p=0.34Carvallodeath, p=0.05Khandeath, p<0.05Chacharno recov., p=0.50Soto-Becerradeath, p=0.01Mahmuddeath, p=0.12Rajterdeath, p=0.04Carvallocases, p<0.0001Hashimdeath, p=0.27Beheracases, p<0.0001Cadegianideath, p=0.50CamprubíICU, p=1.00Elgazzardeath, p<0.0001Elgazzarcases, p=0.03Spoorthirecov. time, p=0.03Carvallocases, p<0.0001Budhirajadeath, p=0.04Niaeedeath, p=0.001Hellwigcases, p<0.02Bernigauddeath, p=0.08Ahmedsymptoms, p=0.09Chaccoursymptoms, p<0.05Afsarsymptoms, p=0.04Alamcases, p<0.0001Vallejoscases, p<0.0001Babalolaviral+, p=0.11Kirtideath, p=0.12NCT04701710cases, p=0.003Okumuşdeath, p=0.55All studies% Lower Risk% Increased Riskivmmeta.com 1/16/21Probability results fromineffective treatmentSep 30 p<0.011 in 100Oct 13 p<0.0011 in 1 thousandNov 4 p<0.00011 in 10 thousandNov 13 p<0.000011 in 100 thousandNov 18 p<0.0000011 in 1 millionDec 2 p<0.00000011 in 10 millionJan 91 in 1 billion
Figure 1. A. Random effects meta-analysis excluding late treatment. Simplified dosages are shown for comparison, these are the total dose in the first two days for treatment, and the monthly dose for prophylaxis, for a 70kg person. For full details 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 only, and for Randomized Controlled Trials (RCTs) only.
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 and 7 show forest plots for a random effects meta-analysis of all studies with pooled effects, and for studies reporting mortality results only. Table 1 summarizes the results.
Treatment timeNumber of studies reporting positive results Total number of studiesPercentage of studies reporting positive results Probability of an equal or greater percentage of positive results from an ineffective treatmentRandom effects meta-analysis results
Early treatment 8 8 100% 0.0039 0.0039
1 in 256
85% improvement
RR 0.15 [0.06‑0.37] p < 0.0001
Late treatment 14 14 100% 0.000061 6.1e-05
1 in 16 thousand
46% improvement
RR 0.54 [0.39‑0.75] p = 0.00024
Prophylaxis 10 10 100% 0.00098 0.00098
1 in 1 thousand
90% improvement
RR 0.10 [0.04‑0.23] p < 0.0001
All studies 32 32 100% 0.00000000023 2.3e-10
1 in 4 billion
77% improvement
RR 0.23 [0.16‑0.34] 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 1/16/21
Figure 3. Results by treatment stage.
100+ 75 50 25 25 50 75 100 Espitia-Hernandezviral+, p<0.0001Carvallodeath, p=0.05Cadegianideath, p=0.50Ahmedsymptoms, p=0.09Chaccoursymptoms, p<0.05Afsarsymptoms, p=0.04Babalolaviral+, p=0.11Kirtideath, p=0.12Early treatment% Lower Risk% Increased Riskivmmeta.com 1/16/21Probability results fromineffective treatmentJan 6 p<0.011 in 100
100+ 75 50 25 25 50 75 100 Gorialdeath, p=1.00Podderrecov. time, p=0.34Khandeath, p<0.05Chacharno recov., p=0.50Soto-Becerradeath, p=0.01Mahmuddeath, p=0.12Rajterdeath, p=0.04Hashimdeath, p=0.27CamprubíICU, p=1.00Elgazzardeath, p<0.0001Spoorthirecov. time, p=0.03Budhirajadeath, p=0.04Niaeedeath, p=0.001Okumuşdeath, p=0.55Late treatment% Lower Risk% Increased Riskivmmeta.com 1/16/21Probability results fromineffective treatmentOct 8 p<0.051 in 20Oct 13 p<0.011 in 100Nov 13 p<0.0011 in 1 thousandJan 12 p<0.00011 in 10 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<0.0001Elgazzarcases, p=0.03Carvallocases, p<0.0001Hellwigcases, p<0.02Bernigauddeath, p=0.08Alamcases, p<0.0001Vallejoscases, p<0.0001Prophylaxis% Lower Risk% Increased Riskivmmeta.com 1/10/21Probability results fromineffective treatmentNov 17 p<0.051 in 20Nov 28 p<0.011 in 100
Figure 5. Chronological history of prophylaxis results.
00.250.50.7511.251.51.752+Espitia-Hernandez0.03[0.01-0.11]12mgviral-35RRCIDoseNCarvallo0.12[0.01-1.06]36mgdeath45Cadegiani0.22[0.01-4.48]28mgdeath247Ahmed (RCT)0.15[0.01-2.70]24mgsymptoms36Chaccour (RCT)0.44[0.16-1.17]28mgsymptoms24Afsar0.08[0.00-1.32]24mgsymptoms90Babalola (RCT)0.36[0.10-1.27]12mgviral-60Kirti (RCT)0.11[0.01-2.05]24mgdeath112Tau​2 = 0.58; I​2 = 39.2%Early0.15[0.06-0.37]649 patients85% improvementGorial0.29[0.01-5.76]14mgdeath87Podder (RCT)0.84[0.55-1.12]14mgrecovery62Khan0.13[0.02-1.01]12mgdeath248Chachar (RCT)0.90[0.44-1.83]36mgrecovery50Soto-Becerra0.83[0.71-0.97]14mgdeath2,833Mahmud (RCT)0.14[0.01-2.73]12mgdeath363Rajter0.54[0.27-0.99]14mgdeath196Hashim (RCT)0.33[0.07-1.60]28mgdeath140Camprubí0.67[0.13-3.35]14mgICU admission26Elgazzar (RCT)0.08[0.02-0.35]56mgdeath400Spoorthi0.79[0.62-1.01]n/arecovery100Budhiraja0.01[0.00-0.15]n/adeath976Niaee (RCT)0.18[0.06-0.55]28mgdeath180Okumuş (RCT)0.67[0.27-1.64]28mgdeath60Tau​2 = 0.14; I​2 = 61.6%Late0.54[0.39-0.75]5,721 patients46% improvementShouman (RCT)0.09[0.03-0.23]18mgsymp. case304Carvallo0.04[0.00-0.63]2mgcase229Behera0.50[0.31-0.73]21mgcase372Elgazzar (RCT)0.20[0.04-0.89]28mgcase200Carvallo0.00[0.00-0.02]12mgcase1,195Hellwig0.22[0.05-0.89]14mgcaseBernigaud0.01[0.00-0.10]28mgdeath138Alam0.09[0.04-0.24]12mgcase118Vallejos0.21[0.09-0.50]12mgcase873NCT04701710 (RCT)0.05[0.00-0.89]12mgcase234Tau​2 = 1.28; I​2 = 86.5%Prophylaxis0.10[0.04-0.23]3,663 patients90% improvementAll studies0.23[0.16-0.34]10,033 patients77% improvementAll ivermectin COVID-19 studiesivmmeta.com 1/16/21Tau​2 = 0.61; I​2 = 83.6%; Z = 7.60 (p < 0.0001)Lower RiskIncreased Risk
Figure 6. Random effects meta-analysis for all studies.
00.250.50.7511.251.51.752+Carvallo0.12[0.01-1.06]36mg45RRCIDoseNCadegiani0.22[0.01-4.48]28mg247Kirti (RCT)0.11[0.01-2.05]24mg112Tau​2 = 0.00; I​2 = 0.0%Early0.14[0.03-0.62]404 patients86% improvementGorial0.29[0.01-5.76]14mg87Khan0.13[0.02-1.01]12mg248Soto-Becerra0.83[0.71-0.97]14mg2,833Mahmud (RCT)0.14[0.01-2.73]12mg363Rajter0.54[0.27-0.99]14mg196Hashim (RCT)0.33[0.07-1.60]28mg140Elgazzar (RCT)0.08[0.02-0.35]56mg400Budhiraja0.01[0.00-0.15]n/a976Niaee (RCT)0.18[0.06-0.55]28mg180Okumuş (RCT)0.67[0.27-1.64]28mg60Tau​2 = 0.56; I​2 = 73.0%Late0.30[0.16-0.57]5,483 patients70% improvementBernigaud0.01[0.00-0.10]28mg138Tau​2 = 0.00; I​2 = 0.0%Prophylaxis0.01[0.00-0.10]138 patients99% improvementAll studies0.22[0.11-0.42]6,025 patients78% improvementAll ivermectin COVID-19 mortality resultsivmmeta.com 1/16/21Tau​2 = 0.76; I​2 = 73.7%; Z = 4.55 (p < 0.0001)Lower RiskIncreased Risk
Figure 7. Random effects meta-analysis for mortality results only.
Randomized Controlled Trials (RCTs)
Results restricted to Randomized Controlled Trials (RCTs) are shown in Figure 8, 9, and 10, and Table 2. RCT results are similar to non-RCT results. Evidence shows that non-RCT trials can also provide reliable results. [Concato] find that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. [Anglemyer] summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. [Lee] shows that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias could have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see [Deaton, Nichol].
00.250.50.7511.251.51.752+non-RCTsRandomized Controlled Trialsmin, Q1, median, Q3, maxLower RiskIncreased Riskivmmeta.com 1/16/21
100+ 75 50 25 25 50 75 100 Shoumansymp. case, p<0.001Podderrecov. time, p=0.34Chacharno recov., p=0.50Mahmuddeath, p=0.12Hashimdeath, p=0.27Elgazzardeath, p<0.0001Elgazzarcases, p=0.03Niaeedeath, p=0.001Ahmedsymptoms, p=0.09Chaccoursymptoms, p<0.05Babalolaviral+, p=0.11Kirtideath, p=0.12NCT04701710cases, p=0.003Okumuşdeath, p=0.55Randomized Controlled Trials% Lower Risk% Increased Riskivmmeta.com 1/16/21Probability results fromineffective treatmentOct 26 p<0.051 in 20Nov 13 p<0.011 in 100Dec 7 p<0.0011 in 1 thousandJan 12 p<0.00011 in 10 thousand
Figure 8. Randomized Controlled Trials. The distribution of results for RCTs is similar to the distribution for all other studies.
00.250.50.7511.251.51.752+Ahmed (RCT)0.15[0.01-2.70]24mgsymptoms36RRCIDoseNChaccour (RCT)0.44[0.16-1.17]28mgsymptoms24Babalola (RCT)0.36[0.10-1.27]12mgviral-60Kirti (RCT)0.11[0.01-2.05]24mgdeath112Tau​2 = 0.00; I​2 = 0.0%Early0.35[0.16-0.77]232 patients65% improvementPodder (RCT)0.84[0.55-1.12]14mgrecovery62Chachar (RCT)0.90[0.44-1.83]36mgrecovery50Mahmud (RCT)0.14[0.01-2.73]12mgdeath363Hashim (RCT)0.33[0.07-1.60]28mgdeath140Elgazzar (RCT)0.08[0.02-0.35]56mgdeath400Niaee (RCT)0.18[0.06-0.55]28mgdeath180Okumuş (RCT)0.67[0.27-1.64]28mgdeath60Tau​2 = 0.44; I​2 = 59.3%Late0.41[0.21-0.80]1,255 patients59% improvementShouman (RCT)0.09[0.03-0.23]18mgsymp. case304Elgazzar (RCT)0.20[0.04-0.89]28mgcase200NCT04701710 (RCT)0.05[0.00-0.89]12mgcase234Tau​2 = 0.00; I​2 = 0.0%Prophylaxis0.09[0.06-0.15]738 patients91% improvementAll studies0.27[0.15-0.51]2,225 patients73% improvementAll ivermectin COVID-19 Randomized Controlled Trials (RCTs)ivmmeta.com 1/16/21Tau​2 = 0.84; I​2 = 72.3%; Z = 4.10 (p < 0.0001)Lower RiskIncreased Risk
Figure 9. Random effects meta-analysis for Randomized Controlled Trials only.
00.250.50.7511.251.51.752+non-RCTs excluding late treatmentRCTs excluding late treatmentmin, Q1, median, Q3, maxLower RiskIncreased Riskivmmeta.com 1/16/21
100+ 75 50 25 25 50 75 100 Shoumansymp. case, p<0.001Elgazzarcases, p=0.03Ahmedsymptoms, p=0.09Chaccoursymptoms, p<0.05Babalolaviral+, p=0.11Kirtideath, p=0.12NCT04701710cases, p=0.003Randomized Controlled Trials (excluding late treatment)% Lower Risk% Increased Riskivmmeta.com 1/16/21
Figure 10. RCTs excluding late treatment.
Treatment timeNumber of studies reporting positive results Total number of studiesPercentage of studies reporting positive results Probability of an equal or greater percentage of positive results from an ineffective treatmentRandom effects meta-analysis results
Randomized Controlled Trials 14 14 100% 0.000061 6.1e-05
1 in 16 thousand
73% improvement
RR 0.27 [0.15‑0.51] p < 0.0001
Randomized Controlled Trials (excluding late treatment) 7 7 100% 0.0078 0.0078
1 in 128
83% improvement
RR 0.17 [0.08‑0.36] p < 0.0001
Table 2. Summary of RCT results.
Exclusions
To avoid bias in the selection of studies, we include all studies in the main analysis. Here we show the results after excluding studies with critical issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available.
[Soto-Becerra] is a database analysis covering anyone with ICD-10 COVID-19 codes, which includes asymptomatic PCR+ patients. Therefore many patients in the control group are likely asymptomatic with regards to SARS-CoV-2, but in the hospital for another reason. For those that had symptomatic COVID-19, there is also likely significant confounding by indication. Several factors are consistent with this - all treatments are worse than the control group at 30 days, KM curves show that more than the total excess mortality at 30 days occurred on day 1, and at the latest followup all treatments show lower mortality than control. The machine learning system used also appears over-parameterized and likely to result in significant overfitting and inaccurate results. Note that this study provides both 30 day mortality and weighted KM curves up to day 43 for ivermectin, we use the day 43 results as per our protocol. [Vallejos] reports prophylaxis results, however only very minimal details are currently available in a news report. We include these results for additional confirmation of the efficacy observed in other trials, however this study is excluded here. [Hellwig] provide an analysis of African countries and COVID-19 cases as a function of whether widespread prophylactic use of ivermectin is used for parasitic infections. Since this is a different kind of study to the typical trial, it is excluded here. [Krolewiecki] show a concentration dependent antiviral activity of ivermectin whereby the viral decay rate for patients with ivermectin >160ng/mL was 0.64 log10 copies/reaction/day versus 0.13 for control. However, they do not provide the results for the entire treatment group vs. control.
Summaring, the studies excluded are as follows, and the resulting forest plot is shown in Figure 11.
[Carvallo], control group formed from cases in the same hospital not in the study.
[Hellwig], not a typical trial, analysis of African countries that used or did not use ivermectin prophylaxis for parasitic infections.
[Soto-Becerra], substantial unadjusted confounding by indication, includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
[Vallejos], detail too minimal.
00.250.50.7511.251.51.752+Espitia-Hernandez0.03[0.01-0.11]12mgviral-35RRCIDoseNCadegiani0.22[0.01-4.48]28mgdeath247Ahmed (RCT)0.15[0.01-2.70]24mgsymptoms36Chaccour (RCT)0.44[0.16-1.17]28mgsymptoms24Afsar0.08[0.00-1.32]24mgsymptoms90Babalola (RCT)0.36[0.10-1.27]12mgviral-60Kirti (RCT)0.11[0.01-2.05]24mgdeath112Tau​2 = 0.80; I​2 = 47.3%