What We Are Learning From the Randomized Controlled Clinical Trial

By Dale Bredesen, M.D., Chief Scientific Officer for Apollo Health

This month will mark the completion of the Evanthea Trial, a randomized, controlled clinical trial comparing the efficacy of the precision medicine protocol we first described in 2013, Next generation therapeutics for Alzheimer’s disease, and published as initial case studies in 2014, Reversal of cognitive decline: A novel therapeutic program, to the standard of care for treatment of Alzheimer’s, with patients being treated at the stage of mild cognitive impairment or early dementia (the same stages as those treated in trials for the new drugs that target amyloid, i.e., Leqembi and Kisunla). We initially dubbed this protocol MEND, for metabolic enhancement for neurodegeneration, but the protocol goes far beyond just metabolic enhancement, and it was subsequently renamed ReCODE for reversal of cognitive decline.

This is the first randomized controlled trial of precision medicine for Alzheimer’s disease in which contributors such as biotoxins, oral microbiome, and tick-borne illnesses have been sought and, when identified, treated. The trial has been conducted at six sites, each with an outstanding functional medicine physician: Dr. Kat Toups (Walnut Creek, CA), Dr. Ann Hathaway (San Rafael, CA), Dr. Craig Tanio (Hollywood, FL), Dr. Nate Bergman (Rocky River, OH), Dr. Kristine Burke (Folsom, CA), and Dr. David Haase (Nashville, TN). Diana Merriam and her Four Winds Foundation have provided very generous funding for this clinical trial.

The trial has collected extensive data, including quantitative neuropsychological testing, genetics, epigenetics, Alzheimer’s biomarkers, imaging with volumetrics, oral and gut microbiome data, metabolic markers, exposure to a wide range of toxins and toxicants, chronic infections, vascular parameters, hormone status, and other biochemical parameters. These data will likely be valuable for data mining for years to come and should provide new insights into the pathophysiology and optimal treatment for Alzheimer’s disease. Meanwhile, however, the cognitive testing is virtually complete, and we are already learning important lessons from these initial trial data:

•Effect size: The protocol group did far better than the standard of care group, with statistically significant improvements in overall cognitive index, memory scores, executive function, and other cognitive tests. A comparison of the effect sizes (how much impact the treatment had) between our trial and others showed that our trial led to a greater effect than any other—6.5 times the effect size of Leqembi, and 3.5 times the effect size of Kisunla. These results show that our approach is more effective than any other to date.

•The bounce: One site that completed treatment early (Dr. Tanio) has already compared the status of the control group during the trial to the six months after trial completion, when this group was offered to switch to the precision medicine protocol. What he found was striking: after declining for nine months on the standard of care, these patients shot up with markedly improved cognitive scores after only six months on the protocol. This is a very promising finding.

•Importance of site: When the data from the six clinical sites were analyzed separately, it turned out that four of the six sites had produced outstanding improvements in cognition, but the other two had almost no improvement — at those two sites, the standard of care control group did just as well as the protocol treatment group. In one case, this was likely because the physician relegated the treatment to an untrained junior physician. Still, whatever the cause, the implication is clear: just as in surgical procedures (and unlike prescription pad medicine), the team of practitioners — from physicians to health coaches to nutritionists to physical trainers — makes all the difference, and thus identifying an experienced and successful team is paramount in achieving the best outcomes.

•The complexities of biomarkers: Blood-based biomarkers have only recently become available for diagnosing and following patients with cognitive decline or risk for decline, and these are offered as BrainScan, which utilizes the most sensitive testing for p-tau 217, provided by Neurocode. This same Neurocode group, led by Dr. Hans Frykman, evaluated the biomarkers in the Evanthea Trial, and although not all data are in yet, we have already seen that there are some complexities in these tests: for example, in multiple patients who did very well, with marked improvements in cognitive outcomes, their p-tau 217 initially increased (instead of decreasing, as one would expect from the cognitive improvement) in association with weight loss. In other patients, one baseline biomarker may have been compatible with Alzheimer’s, but another has fallen within the normal range — perhaps simply because the patient was still in the earliest phase of the disease. The good news is that, overall, the markers improved in association with cognitive improvement.

There are mountains of data yet to be analyzed, and so much to be learned from this trial. My hope is that this precision medicine trial, and others like it in the future, will bring us all a major step closer to reducing the societal burden of neurodegenerative disease.

The insights shared here are based on preliminary observations from the Evanthea clinical trial. Full data analysis and peer-reviewed publication are in progress, and final results will be shared as soon as they are available.