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| Together Trial (News) | |||
| Early Treatment of COVID-19 with Repurposed Therapies: The TOGETHER Adaptive Platform Trial | |||
| Preliminary report from the Together Trial showing mortality RR 0.82 [0.44-1.52].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 [1]. Since overall treatment improves over time, and because the distribution of variants continually changes and shows significant differences in outcomes, this invalidates the randomization of the trial. (Confounding by time is common is COVID-19 studies and has often obscured efficacy because more treatment group patients were earlier when overall treatment protocols were significantly worse). Minas Gerais statistics show a period of declining CFR shortly after the time of excess assignment to ivermectin. The total numbers for the ivermectin and placebo groups also 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 [2, 3]. Treatment was administered on an empty stomach, greatly reducing expected tissue concentration 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 [4], 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.There is 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 is required.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).Trial design, analysis, and presentation, along with previous public and private statements suggest investigator bias. Design: including very late treatment, additional day before administration, including low-risk patients, 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" [5, 6]. Prior statements: [7].There are two published protocols, both are called "version 1", we refer to them as 1A (3/11/21 [8]) and 1B (8/5/21 [9]).1B deletes:- subgroup analysis by treatment delay. - "Amendments to the protocol, except when necessary to eliminate an immediate danger to participants, should be made only with the prior approval of the steering committee. Each applicable regulatory authority and EC must review and approve the amendments before they are implemented."1B adds: "we hypothesize that younger patients will benefit more than older patients"If you are a trial participant please contact us below. For other issues see: [10, 11].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 [12].Cytel Inc. - another statistical modelling company that helps pharmaceutical companies get approval - they work very closely with Pfizer [13].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 [14]. |