A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease

Abstract

Background: Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD.

Objectives: To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement.

Methods: The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (³¹ P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment.

Results: UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain ³¹ P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups.

Conclusions: High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: 31P-MR spectroscopy; UDCA; neuroprotection; supervised gait analysis; ursodeoxycholic acid.

Figure 1:. ³¹Phosphorus Magnetic Resonance voxel localisation, example spectra and results.

Sagittal (A), coronal (B) and axial (C) images demonstrating spectroscopic grid positioning for the midbrain voxels. (D) Example spectrum obtained from the midbrain of an UP study participant. Change from baseline to week 48 in key ³¹P-MRS parameters from the midbrain for; (E) ΔG_ATP and (F) inorganic phosphate; purple diamond and error bars signify mean ± standard deviation; P values depicted on each panel above the bar are for the significance of the estimated treatment coefficient with UDCA as assessed by linear regression. UDCA n=16, placebo n=9 except panel (E) where placebo n=8 due to an excluded magnesium value prior to unblinding required for calculation of ΔG_ATP. PME=phosphomonoesters, PDE= phosphodiesters, Pi= inorganic phosphate, PCr= phosphocreatine, γ-ATP= gamma adenosine triphosphate, α-ATP= gamma adenosine triphosphate, β-ATP= gamma adenosine triphosphate, ΔG_ATP = Gibbs free energy of ATP hydrolysis.

Figure 2:. Consort flowchart of enrollment, allocation and follow-up assessments performed.

Analysis used an intention-to-treat population therefore all participants randomised were included in the analysis dataset. Details of key secondary outcome assessments are included to demonstrate data completeness.

Figure 3:. Supervised gait analysis.

Comparison of changes in cadence from baseline to week 48 (placebo n= 6, UDCA n = 12). Data is shown at the individual level with each line representing a different participant. Cadence improved in the UDCA group (median change +1.5 step/min) but deteriorated in the placebo group (median change −4.5 step/min). This was significant at the group level (P=0.0253) as assessed with the Mann-Whitney U test.