Lay summary by Louise Heywood, reviewed by Dr Tom Payne, and by a Parkinson’s Disease Lay Panel.
Background
Mitochondria act as the batteries of the cell, producing high amounts of energy for cells to function properly. In Parkinson’s, these batteries produce less energy, resulting in brain cells starving and dying. Therefore, one hope to slow down the progression of Parkinson’s is to use medication to keep mitochondria healthy. Ursodeoxycholic acid (UDCA) is commonly used as a treatment for liver disease, making it an ideal candidate for drug repurposing – using existing drugs to treat different conditions. This study was a Phase II clinical trial, where patients were randomly assigned to either UDCA treatment or a placebo drug, with neither participants nor doctors knowing which participants were taking UDCA. The study took place across two centres, one at Sheffield Teaching Hospitals (STH) and one at University College London (UCL) Hospitals. All participants had been diagnosed with Parkinson’s for less than three years.
Why is the study important?
There are currently no approved treatments for Parkinson’s that can prevent the loss of affected brain cells nor alter the progression of the condition – the available treatments can help reduce symptoms, but not the underlying causes. UDCA is a potential ‘neuroprotective’ drug that is hoped can prevent further loss of brain cells, and as such, represents an important step forward in the treatment of Parkinson’s. The first step to getting a new treatment to patients is to assess its safety and efficacy in clinical trials.
What did the authors do and how did they do it?
The trial consisted of 31 total participants randomly assigned to either UDCA treatment or placebo group with 20 taking UDCA and 10 taking a placebo. Participants remained on the treatments for 48 weeks, followed by an 8-week ‘wash-out’ period where treatment was stopped, to assess the longevity of UDCAs effects.
The main assessments were regarding safety and tolerability, but the study also looked at the effects of UDCA on the brain, and on Parkinson’s movement symptoms. To confirm that UDCA was having an effect on the brain a type of brain scan known as phosphorus-31 magnetic resonance spectroscopy was used. This is a specific brain scan that can measure the changes in levels of energy in the brain. Changes in movement symptoms were assessed using the standard clinical rating scale (MDP-UPDRS-III) and a digital, wearable, sensor-based system (Sheffield cohort only).
What are the results?
One participant completely withdrew from the study, due to problems swallowing, the high number of capsules, and was subsequently replaced. Another two participants stopped taking their tablets early, but still completed the study. This was due to the burden of taking so many capsules in addition to their existing medication. There were two serious adverse events during the trial, both of which affected the same patient in the placebo group, and in total 24 adverse reactions in 14/31 participants, affecting 10 UDCA participants and 4 placebo participants. The most frequently reported side effects of UDCA were mild diarrhoea and mild nausea, which required no treatment and was of short (24-72 hr) duration, therefore the authors felt that the 30 mg/kg dose of UDCA daily was well-tolerated and safe.
The brain scans of participants taking UDCA showed that there was a potentially increased efficiency of energy breakdown in the brains of UDCA participants, suggesting that UDCA is having a positive effect on Parkinson’s. The sensor-based movement analysis showed that participants taking UDCA had an increase in steps per minute when walking, and a reduction in time taken to make a full stride, and the time stood on both feet while walking when compared to those taking placebo. All of this would tentatively suggest an improvement in walking ability in the UDCA group, however the small number of participants means that the results must be approached with caution. However, the MDP-UPDRS-III clinical rating scale showed that both those taking UDCA and placebo experienced an improvement in their Parkinson’s symptoms during the study.
The study also looked at effects of UDCA on non-motor symptoms, such as depression; on a depression rating scale (MADRS), scores showed a small but important increase in the UDCA group, compared to the placebo group, though scores were overall still far below the cut off that indicates depression.
What do the findings mean going forward for people with the disease?
The study shows an improvement, or comparatively slower decline, in walking ability in the UDCA group, in addition to a slower progression of movement symptoms on the standard rating scale, suggesting UDCA has potential as a new Parkinson’s drug. Though the results of this study seem promising for the safety of UDCA, which was its primary aim, the study is limited by its small number of participants, and therefore a larger trial is needed to confirm whether UDCA can slow down the progression of Parkinson’s.
This study can be found at Wiley Online Library DOI: 10.1002/mds.29450
Paper title A Double-Blind, Randomised, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson’s Disease
Author list Payne, T., Appleby, M., Buckley, E., van Gelder, L. M. A., Mullish, B. H., Sassani, M., Dunning, M. J., Hernandez, D., Scholz, S. W., McNeill, A., Libri, V., Moll, S., Marchesi, J. R., Taylor, R., Su, L., Mazza, C., Jenkins, T. M., Foltynie, T. and Bandmann, O.
Publication details including date of publication. Movement Disorders, Published May 2023