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All Studies   Meta Analysis    Recent:   
0 0.5 1 1.5 2+ Mortality 67% Improvement Relative Risk Escalation of care 61% Escalation of care with po.. 34% Deterioration by >= 2 point.. 43% primary Fever post randomization 25% Unresolved symptoms at.. 15% Lack of resolution of symp.. 7% post-hoc primary Median time to resolution.. 17% no CI Ivermectin  López-Medina et al.  EARLY TREATMENT  DB RCT Is early treatment with ivermectin beneficial for COVID-19? Double-blind RCT 398 patients in Colombia (July - November 2020) Lower mortality (p=0.5) and progression (p=0.11), not sig. c19ivm.org López-Medina et al., JAMA, March 2021 Favors ivermectin Favors control

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial

López-Medina et al., JAMA, doi:10.1001/jama.2021.3071
Mar 2021  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
 
*, now known with p < 0.00000000001 from 100 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments. c19ivm.org
Phone survey based RCT with low risk patients, 200 ivermectin and 198 control, showing lower mortality, lower disease progression, lower treatment escalation, and faster resolution of symptoms with treatment, without reaching statistical significance. Authors find the results of this trial alone do not support the use of ivermectin. However the effects are all positive, especially for serious outcomes which are unable to reach statistical significance with the very small number of events in the low risk population.
An open letter, signed by >100 physicians, concluding this study is fatally flawed can be found at jamaletter.com.
With the low risk patient population, there is little room for improvement with an effective treatment - 59/57% (IVM/control) recovered within the first 2 days to either "no symptoms" or "not hospitalized and no limitation of activities"; 73/69% within 5 days. Less than 3% of all patients ever deteriorated.
The primary outcome was changed mid-trial, it was originally clinical deterioration, which is more meaningful, and shows greater benefit. The new outcome of resolution of symptoms includes "not hospitalized and no limitation of activities" as a negative outcome and is not very meaningful in terms of assessing how much treatment reduces serious outcomes. Using this measure could completely invalidate results - for example a treatment that eliminates all COVID-19 symptoms but has a temporary minor adverse event could be seen as worse.
Authors state that "preliminary reports of other randomized trials of ivermectin as treatment for COVID-19 with positive results have not yet been published in peer-reviewed journals", however there were 8 peer-reviewed RCTs with positive effects published prior to this paper(and 19 total peer-reviewed studies with positive effects).
Authors advised taking ivermectin on an empty stomach, reducing lung tissue concentration by ~2.5x Guzzo.
76 patients were excluded due to control patients receiving ivermectin. However, there was a similar percentage of adverse events like diarrhea, nausea, and abdominal pain in both treatment and control groups. These are potential non-serious side effects of treatment and suggest that it is possible that many more control patients received some kind of treatment.
No pre-registered protocol documentation has been found, the same organization is associated with other COVID trials with extremely high financial conflicts of interest with this trial, and the official registration shows a different code to the paper (IVE-PA_CEIP vs. PI-CEP-1390) twitter.com.
Ivermectin was widely used in the population and available OTC at the time of the study. The paper claims that patients were excluded if they used ivermectin within the last 5 days, however this conflicts with the trial registration which shows that use of ivermectin within the previous 2 days was an exclusion criterion. A post-hoc change to 5 days was made on December 16, 2020 clinicaltrials.gov, twitter.com (B), which is after enrollment ended (July 15 to November 30, 2020). Ivermectin may retain efficacy far beyond 2 or 5 days. Note that, with 75% of patients having symptoms for 4+ days at baseline, the trial registration allows patients to take ivermectin for a few days after symptoms and then join the placebo arm two days later twitter.com (C).
This study reportedly has an ethical issue whereby participants were told the study drug was "D11AX22" trialsitenews.com. The editor-in-chief of JAMA initially offered to help with this issue, but later indicated that "JAMA does not review consent forms", however the lead author reportedly confirmed the issue francesoir.fr, trialsitenews.com (B), trialsitenews.com (C).
The study protocol specifically allows "the use of other treatments outside of clinical trials". The paper provides no information on what other treatments were used, but other treatments were commonly used at the time. Additionally, the control group did about 5x better than anticipated for deterioration, also suggesting that the control patients used some kind of treatment. Patients that enroll in such a study may be more likely to learn about and use other treatments, especially since they do not know if they are receiving the study medication.
The study protocol was amended 4 times. Amendments 2-4 are provided but amendment 1 is missing. Amendment 2 increased the inclusion criteria to within 7 days of onset, including more later stage patients and reducing the expected effectiveness. The trial protocol lists “the duration of supplemental oxygen” as an outcome but the results for this outcome are missing.
RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that believe they need treatment are more likely to decline participation and take the intervention Yeh, i.e., RCTs are more likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin was available OTC and very widely known and used.
Grants and/or personal fees, including in some cases during the conduct of the study, were provided by Sanofi Pasteur, GlaxoSmithKline, Janssen, Merck, and Gilead. For more details see trialsitenews.com (D).
For other confounding issues see osf.io and additional issues can be found in the comments of the article jamanetwork.com. Re-analysis of the raw data has been reported to show a significant positive effect twitter.com (D).
Most data was collected via surveys, without physical examination. 87% medication adherence. NCT04405843 (history).
This is the 19th of 47 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.0000002. This is the 41st of 100 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 1 sextillion).
This study is excluded in the after exclusion results of meta analysis: strong evidence of patients in the control group self-medicating, ivermectin widely used in the population at that time, and the study drug identity was concealed by using the name D11AX22.
risk of death, 66.8% lower, RR 0.33, p = 0.50, treatment 0 of 200 (0.0%), control 1 of 198 (0.5%), NNT 198, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of escalation of care, 60.8% lower, RR 0.39, p = 0.11, treatment 4 of 200 (2.0%), control 10 of 198 (5.1%), NNT 33, odds ratio converted to relative risk.
risk of escalation of care with post-hoc <12h exclusion, 34.3% lower, RR 0.66, p = 0.52, treatment 4 of 200 (2.0%), control 6 of 198 (3.0%), NNT 97, odds ratio converted to relative risk.
risk of deterioration by >= 2 points on an 8-point scale, 43.1% lower, RR 0.57, p = 0.37, treatment 4 of 200 (2.0%), control 7 of 198 (3.5%), NNT 65, odds ratio converted to relative risk, primary outcome.
risk of fever post randomization, 24.8% lower, RR 0.75, p = 0.38, treatment 16 of 200 (8.0%), control 21 of 198 (10.6%), NNT 38, odds ratio converted to relative risk.
risk of unresolved symptoms at day 21, 15.3% lower, RR 0.85, p = 0.53, treatment 36 of 200 (18.0%), control 42 of 198 (21.2%), NNT 31, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, Cox proportional-hazard model.
lack of resolution of symptoms, 6.5% lower, HR 0.93, p = 0.53, treatment 200, control 198, inverted to make HR<1 favor treatment, post-hoc primary outcome.
relative median time to resolution of symptoms, 16.7% better, relative time 0.83, treatment 200, control 198.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
López-Medina et al., 4 Mar 2021, Double Blind Randomized Controlled Trial, Colombia, peer-reviewed, median age 37.0, 19 authors, study period 15 July, 2020 - 30 November, 2020, average treatment delay 5.0 days, dosage 300μg/kg days 1-5.
This PaperIvermectinAll
Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19
MD, MSc Eduardo López-Medina, MD Pío López, MD; Isabel C Hurtado, MD, MPH, DrPH Diana M Dávalos, MD, MPhil Oscar Ramirez, MD Ernesto Martínez, MD Jesus A Díazgranados, MD José M Oñate, MD, MS Hector Chavarriaga, MD Sócrates Herrera, PhD Beatriz Parra, PhD Gerardo Libreros, MD Roberto Jaramillo, MD; Dilian Ana C Avendaño, Dilian F Toro, DrPH Miyerlandi Torres, MD Maria C Lesmes, MD Carlos A Rios, MD Isabella Caicedo
JAMA, doi:10.1001/jama.2021.3071
IMPORTANCE Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit. OBJECTIVE To determine whether ivermectin is an efficacious treatment for mild COVID-19. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state's health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020. INTERVENTION Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200). MAIN OUTCOMES AND MEASURES Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected. RESULTS Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 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 = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group). CONCLUSION AND RELEVANCE 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, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.
Funding/Support: This study received an unrestricted grant from Centro de Estudios en Infectología Pediátrica (grant ScDi823). Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Group Information
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