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Ivermectin study #110 of 116   Meta Analysis
8/6 Early treatment study
Together Trial (News)
Early Treatment of COVID-19 with Repurposed Therapies: The TOGETHER Adaptive Platform Trial
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Preliminary report from the Together Trial showing mortality RR 0.82 [0.44-1.52] and combined extended ER observation or hospitalization RR 0.91 [0.69-1.19].
The trial randomization chart suggests major problems and does not match the protocol. Trial week 43, the first week for 3 dose ivermectin, shows ~3x patients assigned to ivermectin vs. placebo [reddit.com]. Treatment efficacy can vary significantly over time due to overall improvement in protocols, changes in public awareness, and changes in the distribution of variants. Minas Gerais statistics show a period of declining CFR shortly after the time of excess assignment to ivermectin. This introduces confounding by time, which is common in COVID-19 studies and has often obscured efficacy because more patients in the treatment group were earlier in time when overall treatment protocols were significantly worse. According to this analysis [reddit.com], the total number of patients for the ivermectin and placebo groups do not appear to match the totals in the presentation — reaching the number reported for ivermectin would require including some of the patients assigned to single dose ivermectin. Reaching the placebo number requires including placebo patients from the much earlier ivermectin single dose period, and from the early two week period when zero ivermectin patients were assigned.
Treatment delay is currently unknown, however the protocol allows very late inclusion and a companion trial reported mostly late treatment. Overall mortality is high for 18+ outpatients. Results may be impacted by late treatment, poor SOC, and may be specific to local variants [Faria, Nonaka, Sabino]. Treatment was administered on an empty stomach, greatly reducing expected tissue concentration [Guzzo] and making the effective dose about 1/5th of current clinical practice. The trial was conducted in Minas Gerais, Brazil which had substantial community use of ivermectin [otempo.com.br], and prior use of ivermectin is not listed in the excluson criteria.
Time from symptom onset to randomization is specified as within 7 days. However the schedule of study activities specifies treatment administration only one day after randomization, suggesting that treatment was delayed an additional day for all patients.
This trial uses a soft primary outcome, easily subject to bias and event inflation in both arms (e.g., observe >6 hours independent of indication). There is also an unusual inclusion criteria: "patients with expected hospital stays of <= 5 days". This is similar to "patients less likely to need treatment beyond SOC to recover", and would make it very easy to reduce the effect seen. This is not in either of the published protocols.
The trial took place in an area of Brazil where the Gamma variant was prominent. Brazilian clinicians report that this variant is much more virulent, and that significantly higher dosage and/or earlier treatment is required, as may be expected for variants where the peak viral load is significantly higher and/or reached earlier [Faria, Nonaka].
Trial design, analysis, and presentation, along with previous public and private statements suggest investigator bias. Design: including very late treatment, additional day before administration, operation in a region with high community use, specifying administration on an empty stomach, limiting treatment to 3 days, using soft inclusion criterion and a soft primary outcome, easily subject to bias. Analysis: authors perform analysis excluding events very shortly after randomization for fluvoxamine but not ivermectin, and report viral load results for fluvoxamine but not ivermectin. Presentation: falsely describing positive but not statistically significant effects as "no effect, what so ever" [Amrhein, odysee.com]. Prior statements: [odysee.com].
There are two published protocols, both are called "version 1", we refer to them as 1A (3/11/21 [drive.google.com] ) and 1B (8/5/21 [gatesopenresearch.org]. 1B deletes subgroup analysis by treatment delay, and deletes a statement requiring prior approval for amendments. 1B adds the statement: "we hypothesize that younger patients will benefit more than older patients."
The trial is associated with:
MMS Holdings - a company whose mission includes helping pharmaceutical companies get approval and designing scientific studies that help them get approval. One of their clients is Pfizer [mmsholdings.com].
Cytel Inc. - another statistical modelling company that helps pharmaceutical companies get approval - they work very closely with Pfizer [cytel.com].
One of the senior investigators was Dr. Craig Rayner, President of Integrated Drug Development at Certara - another company with a similar mission to MMS Holdings. They state on their website that: "Since 2014, our customers have received over 90% of new drug and biologic approvals by the FDA." One of their clients is Pfizer [certara.com].
If you are a trial participant please contact us below. For other issues see: [twitter.com, twitter.com (B)].
Together Trial et al., 8/6/2021, Double Blind Randomized Controlled Trial, Brazil, South America, preprint, 1 author, dosage 400μg/kg days 1-3.
risk of death, 18.0% lower, RR 0.82, p = 0.54, treatment 18 of 677 (2.7%), control 22 of 678 (3.2%).
extended ER observation or hospitalization, 9.0% lower, RR 0.91, p = 0.51, treatment 86 of 677 (12.7%), control 95 of 678 (14.0%).
This study is excluded in meta analysis: preliminary report with minimal details.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. For an individual study the most serious outcome may have a smaller number of events and lower statistical signficance, however this provides the strongest evidence for the most serious outcomes when combining the results of many trials.
All 116 studies   Meta Analysis
Please send us corrections, updates, or comments. Vaccines and treatments are both extremely valuable and complementary. All practical, effective, and safe means should be used. 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. Denying the efficacy of any method increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. Treatment protocols for physicians are available from the FLCCC.
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