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AAIC 2021 | Phase III ADMET2 trial of methylphenidate for apathy in Alzheimer’s Disease

Jacobo E. Mintzer, MD, of the Medical University of South Carolina, shares the results of the Phase III ADMET2 trial (NCT02346201) of methylphenidate to reduce apathy in patients with Alzheimer’s disease (AD). Apathy is a syndrome seen in 71% of AD patients, characterized by a lack of expression of emotion, initiative, and interest in surroundings. After two positive short preliminary studies, the Phase III randomized, placebo controlled trial examined the effects of methylphenidate on approximately 200 AD subjects over 6 months. Changes in the neuropsychiatric inventory apathy subscale (NPIa) and clinical global impression of change (CGIC) were assessed as primary outcome measures. At 6 months, the ADCS-CGIC showed that 43.8% of methylphenidate treated participants improved compared with 35.2% receiving placebo, favoring methylphenidate but not reaching statistical significance. A statistically significant difference in NPIa improvement from baseline compared to placebo was observed. Effects of the drug were seen after approximately 2 months of use, and these effects remained after the 6-month period of the study. The information provided is a summary of the presentation given at the AAIC 2021 meeting in Denver, CO on July 29, 2021.

Transcript (edited for clarity)

Apathy is the most common neuropsychiatric symptom observed in dementia, especially in Alzheimer’s disease, with 71% of the people suffering from dementia presenting symptoms of apathy at some point during the disease. Apathy is not just a symptom, but has negative consequences. It causes excess disability in patients, causes increased risk of institutionalization and increased risk of death...

Apathy is the most common neuropsychiatric symptom observed in dementia, especially in Alzheimer’s disease, with 71% of the people suffering from dementia presenting symptoms of apathy at some point during the disease. Apathy is not just a symptom, but has negative consequences. It causes excess disability in patients, causes increased risk of institutionalization and increased risk of death. It also causes increase in burden and stress in caregivers. It’s a common problem with major consequences. Now, we don’t have today any treatment for apathy and until recently we didn’t have a definition. Just to be clear today, we’re talking about apathy and when we talk about apathy, we talk about a syndrome characterized by lack of effect or lack of expression of emotion to positive or negative events. Lack of initiative, lack of interest in their surroundings.

Many people will say, “What’s the difference between apathy and depression?” The two syndromes could not be more different. Depression is a very strong, emotional response that is associated with negative events. It’s a very strong negative emotion. On the other hand, apathy is the lack of emotion. Could not be more different. One is an extreme of emotion on the negative side. The second one is the lack of emotion. Now, what causes apathy? Well, we don’t know the geology of apathy. However, many studies have shown a strong association between deficits in the dopamine catecholamine pathway and the onset of apathy in patients with Alzheimer’s disease. If you were to think about how to treat it, the thinking process will be that you would like to treat with something that will enhance the catecholamine dopaminergic pathway. Now Ritalin happens to be the most studied dopamine catecholamine enhancer in the elderly. Therefore, we choose to study the effects of Ritalin, which is a catecholamine dopamine enhancer, in patients with Alzheimer’s disease that present with apathy.

We did two studies, two preliminary studies, one that was six weeks and the other one was 12 weeks. Each one of the two studies included about 60 subjects. Both studies showed positive results. Therefore, we felt encouraged to move forward to a Phase III trial. Now the goal of the Phase III trial was to do a very similar study with a larger population and in more sites to test generalizability, and also to do it for a longer period of time. In this case, we chose six months. We did manage to recruit 200 subjects, which was what the study was powered for. The primary outcome measures were either the NPIa, the neuropsychiatric inventory apathy subscale, or a modified version with apathy anchored of the CGIC, which is a global clinical scale.

What we found was that the NPIa was very positive, 0.02 p-value. That meant that the study was positive. Because we said either/or rather than and to consider the study positive, we split the answer. Subjects have to be positive in either one of the two considered positive, but have to be at a 0.025 or below. The CGIC came out at 0.048. That was not considered to be a positive outcome. However, there was a very strong association between improvement in NPIa or improvement in apathy and improvement in CGIC. There were also significant association between improvement in apathy and improving in caregiver distress. Both items suggest the presence of a clinical meaningfulness to the results that we saw. It’s not that you have a change in the scale, but actually seems to have a positive effect in the subject and in the caregiver. Now, there were no meaningful side effects. What we call in clinical research adverse events, there were no deaths and no meaningful, serious adverse events. None of those that were present that were considered to be related to the study medication.

We concluded that the treatment from Ritalin, methylphenidate, in patients with Alzheimer’s disease, suffering from apathy is mild to moderately effective, has clinical meaningfulness, and appears to be associated with improvements in clinical response and caregiver distress. Now of interest is that the effects we’re seeing, started to become meaningful in about two months and these strong response remain over the six months period of the study.

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Disclosures

Prof. Mintzer reports the following disclosures:
AARP – Global Council on Brain Health, AARP – Staying Sharp, ACADIA, ACTC/ATRI, Alzheimer’s Association (local and national), BioPharma Connex, Cerevel Therapeutics, Genentech Pharmaceuticals, International Psychogeriatric Association, NeuroQuest, Praxis Pharmaceuticals, Recruitment Partners LLC, Technology Accelerator Company, Elder Court.