A trial designed to give adherence advocates a heart attack

“In the absence of data, we will always make up stories. It’s how we are wired.”

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In an extraordinary turn of events, a recent trial was doomed to failure when an unusual number of patients (n=51 ) randomized to receive active study drugs had no detectable study drug in their blood samples even though they self-reported to have routinely ingested the drug.

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This incident was critical to the trial outcome as the blood was drawn at the end of the study (week 12) together with the primary outcome assessment. What occurred between randomization and the study's conclusion remains very uncertain.

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The trial ‘Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy’[1] was designed to evaluate the efficacy and safety of a combination drug in patients with hypercholesterolemia and a high risk of cardiovascular disease.

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However, a review established that more than half of patients (34/67) from 3 study sites and expected to receive the active study drug, had no detectable study drug in blood samples at the end of week 12. A root cause analysis ruled out any issues with the production or distribution of the study drug or the handling/analysis of pharmacokinetic samples.

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So, what was the explanation?

“Inferential evidence indicated an indeterminate period of time when patients from these three sites were not taking the study drug as directed by the study protocol, which raised concerns about the integrity of any of the data from these three sites.”

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Anyone else confused?

How is it possible that these patients had self-reported to have taken the medication, study investigators confirmed adherence to study drug using returned pill counts and yet there was no detectable drug in their samples? And why was this only picked up at the end of the trial?

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Because of concerns that data from these three sites would not accurately re?ect either the safety or e?cacy of experimental therapy, data from these three sites was simply excluded – how can that be in the best interests of any stakeholder?

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Frankly the whole study is somewhat confusing – even the recruitment strategy seems odd – there were 81 patients recruited from three sites, almost 10-fold the expected recruitment rate planned for the study i.e. 78 sites planned for just 300 patients?

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With reliable adherence data available during the study, it could have been identified in a timely manner that the three sites with high recruitment were not effective in ensuring patients consistently took their study medications.

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And at a cost of around $41,117 per patient for a phase 3 trial, the financial burden of such a failure is significant, but the time and risk associated with recruiting new patients is also substantial. Particularly if lessons have not been learned in terms of monitoring adherence and realigning the study in a more timely, agile way.

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“In the absence of data, we will always make up stories. It’s how we are wired”

Too often here at AARDEX we report and comment on suboptimal trials, primarily where there have been real oversights in terms of measuring adherence leading to unreliable data and incorrect conclusions regarding efficacy and safety. This study is a case in point where there is clearly a real issue with the trial group, and yet, even in the absence of robust data, the trial is deemed to be a success.

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AARDEX is the only mature, robust and proven adherence solution on the market today, one that maximizes the reward, mitigates the risk and delivers resolution for your clinical trial. All delivered with the clarity, integrity and certainty you need to proceed with complete confidence in the exposure-response.?

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[1] https://pubmed.ncbi.nlm.nih.gov/31357887/