Essai de phase 2 de la Tributyrine chez les personnes atteintes de la maladie de Parkinson et des troubles cognitifs (BUTTER2)

Changes in cognition, progressing usually to dementia, are common features of Parkinson disease (PD). These debilitating impairments respond poorly to current anti-dementia treatments and call for novel strategies. Short chain fatty acids (SFCA), in particular butyric acid (BA), are naturally present in the colon as a bacterial product of dietary fiber fermentation. There is renewed interest in SCFAs because of their potential as alternative substrates in brain metabolism, their role in the gut-brain axis, and emerging evidence that interventions promoting SCFA benefit patients with neurodegenerative disorders. Convergent evidence suggests that SFCAs may ameliorate metabolic defects secondary to mitochondrial abnormalities in PD. In addition, the gut-brain axis represents a bidirectional communication complex system involving the vagal and sympathetic nerves and humoral systems. Effects of SCFA on the brain may be indirect and/or direct. For example, fiber-induced SCFA production in the colon may result in vagal nerve-mediated changes affecting the brain. Blood and brain levels of fiber-induced SCFA are naturally very low. SCFAs can be directly administered orally, resulting in higher portal vein and systemic plasma levels that may more potently affect brain functions. Oral butyrate supplementation, however, suffers from several limitations as plasma levels are low because of rapid metabolism. In contrast, tributyrin (the triglyceride of BA) is rapidly absorbed and chemically stable in plasma, diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective BA over time directly within cells. We previously generated target engagement data showing that oral tributyrin, 500 mg three times per day (tid) po, is well tolerated and improves cognition. We also conducted the first [11C]butyrate positron emission tomography (PET) study, demonstrating that tributyrin has direct brain effects, particularly in regions relevant to cognitive functions. Significant systemic anti-inflammatory effects were also observed. A limitation of our preliminary phase 1I target engagement study is the short duration (30 days) and lack of inclusion of people with PD with more severe cognitive impairments, such as dementia. The overarching goal of this project is to perform a parallel group, double-blinded, randomized placebo-controlled phase 2 clinical trial of tributyrin, 500 mg tid po for 90 days, to validate and extend these preliminary observations in a longer duration clinical trial in people with PD with mild cognitive impairment (PD-MCI) or Parkinson disease dementia (PDD). There is critical unmet clinical need to treat people currently affected with PD who have significant cognitive impairments. Our main hypothesis is that oral tributyrin supplementation will improve cognition as well as motor functions, including cognition-dependent postural instability and gait difficulties. Successful completion of this trial would set the stage for a major, multi-center phase III clinical trial aimed at ameliorating this particularly morbid feature of PD.