First Patient Recruited for UK Study of Cholinesterase Inhibitors in Parkinson’s Disease

cholinesterase inhibitors

The first participant has been recruited for a clinical trial in the United Kingdom that will test whether a class of medicines used mainly for dementia can help prevent falls in Parkinson’s disease patients.

Led by the University of Bristol and the Royal United Hospitals (RUH) Bath NHS Foundation Trust, the three-year medical research Phase 3 Cholinesterase Inhibitors to Prevent Falls in Parkinson’s Disease Trial (CHIEF-PD, 2018-003219-23) ultimately will recruit 600 patients across 26 UK hospitals to determine the effectiveness of cholinesterase inhibitors (ChEi) for one of the most disabling complications of Parkinson’s.

Several studies have shown that, mostly due to balance problems caused by the loss of dopamine in the brain, individuals with Parkinson’s are at greater risk of falls, which can be debilitating. In the UK, falls affect roughly 60% of the 127,000 people living with the disease.

“To recruit our first patient is hugely significant and marks the official start of what is a really important study,” Ruth Hamlin, RUH research lead nurse, said in a press release. “While there is no cure for Parkinson’s, our hope is that this research and its eventual findings will help to improve patients’ quality of life.”

Trial participant and UK resident Gitte Dawson was diagnosed with Parkinson’s seven years ago and has experienced multiple falls since then.

“I’m very interested in this research and learning about its findings,” she said. “It’s very practical and doable for a patient like me on a daily basis, which is important because we’ll be taking part for a year.”

Dawson and other trial participants, who must have experienced a fall in the year before joining the trial, will be assigned randomly to take a placebo or a year-long course of a ChEi, both via a patch. Neither researchers nor participants will know which group they’re in. Patients will maintain records of falls.

Funded by a £2.1 million ($2.7 million) National Institute for Health Research grant, the trial is led by Emily Henderson, an RUH consultant geriatrician.

“This research will provide definitive evidence as to the role of these drugs for falls,” Henderson said. “We are working hard to tackle one of the most disabling complications of Parkinson’s and, if successful, this treatment will improve the lives of people living with Parkinson’s now, and has the potential to be tested in other groups of patients who are at high risk of falling.”

Three smaller investigations showed that the inhibitors have the potential to nearly halve the number of falls. Cholinesterase inhibitors block the normal breakdown of acetylcholine (an important brain neurotransmitter), which  restores imbalances in different neurotransmitters in the brain. (A neurotransmitter is a brain chemical that allows nerve cells to communicate.)

“I’m delighted that this trial has now begun, and proud that the RUH is leading with the University of Bristol in such important research that has the potential to benefit people worldwide,” said Tim Craft, the Trust’s director of research and innovation.

Trial results will be published in a research journal. Use this email to obtain more information about the trial.

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GDNF Shows Potential as Neurorestorative Treatment for Parkinson’s

GDNF studied

Infusion of a naturally occurring protein, GDNF, into a motor control area of the brain may restore cells damaged by Parkinson’s disease and ease patients’ symptoms, results from a European clinical trial suggest.

The study, “Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease” was published in the Journal of Parkinson’s Disease.

Evidence shows that glial cell line-derived neurotrophic factor (GDNF) supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease. In animal models of Parkinson’s, GDNF has consistently demonstrated both neuroprotective and neurodegenerative effects when provided continuously.

Researchers developed a three-part clinical trial (EudraCT Number: 2013-001881-40) to study the safety and effectiveness of GDNF infusions in Parkinson’s patients. The trial first recruited six patients to assess the safety of the treatment. Then, 35 more participants entered the nine-month, double blind trial in which half were given monthly infusions of GDNF. The other half received placebo infusions through an implant that delivered the treatment directly to the brain through a port placed behind the ear.

This part of the study showed that patients who received monthly doses of GDNF into their putamen — a brain region involved in movement control that’s deeply damaged in Parkinson’s — had a significant increase of dopamine levels in the brain compared to the placebo group. However, the apparent increase in dopamine levels were not reflected on patients’ clinical status.

“The spatial and relative magnitude of the improvement in the brain scans is beyond anything seen previously in trials of surgically delivered growth-factor treatments for Parkinson’s,” principal investigator Alan L. Whone, PhD, said in a press release. Whone is in Translational Health Sciences, Bristol Medical School, University of Bristol, and Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK,  “This represents some of the most compelling evidence yet that we may have a means to possibly reawaken and restore the dopamine brain cells that are gradually destroyed in Parkinson’s,” he said.

Using the same patient sample (41 subjects, ages 35–75) researchers further assessed the effects of continued (21 patients who had received GDNF) or new (20 patients who had received placebo) exposure to GDNF for another nine months in the open-label extension phase of the trial. Dosing followed the same protocol as before with GDNF infusion given every month.

Although all patients knew they were receiving GDNF, they remained oblivious to what their treatment in the previous study was.

The primary goal of the study was measure the percentage change from parent trial week zero to week 80 (or week 40, depending on the study group) in the “off” state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. As disease progresses, patients experience off periods more frequently. Such episodes are characterized by the reappearance or worsening of symptoms due to diminishing effects of levodopa therapy.

The treatment had no treatment-emergent safety issues, but all patients experienced at least one adverse side effect, including application site infection, headache, back pain, and uncontrollable muscle contraction (dystonia).

By 18 months (all participants had received GDNF), both groups showed a trend toward score reduction, indicating motor function improvement. GDNF also was found safe when administered over this length of time. However, there were no significant differences in off state UPDRS motor score between patients who received GDNF for 18 months and those who received it for nine months only (parent study placebo group).

Importantly, total off time and good-quality “on” time per day improved in both study groups.

In comparison to the beginning of the parent trial, mean total off time per day decreased by an average of 1.5 hours in patients who received GDNF throughout the whole study, and by 0.8 hours in the those who received placebo and GDNF. “Good-quality ON time increased by [an average of 1.6] hours in the GDNF/GDNF group and by [0.5] hours in the placebo/GDNF group,” researchers wrote.

“This trial has shown that we can safely and repeatedly infuse drugs directly into patients’ brains over months or years. This is a significant breakthrough in our ability to treat neurological conditions, such as Parkinson’s, because most drugs that might work cannot cross from the blood stream into the brain due to a natural protective barrier,” said senior author Steven Gill, honorary professor in neurosurgery at the University of Bristol, and designer of the GDNF delivery system (Convection Enhanced Delivery, CED).

“I believe that this approach could be the first neurorestorative treatment for people living with Parkinson’s, which is, of course, an extremely exciting prospect,” Gill stated.

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New €10M Study Looks to Improve Integrated Care for Parkinson’s Patients in the UK and Netherlands

Neupro, UCB, China

The University of Bristol in England is leading a five-year, €10 million study aimed at finding ways to better integrate care for Parkinson’s disease patients while lowering costs, the institution recently announced. 

Over the course of the trial, the new care model is expected to be delivered to about 1,000 Parkinson’s patients in areas served by the Royal United Hospitals in Bath, England. At the same time, similar healthcare innovations will be implemented in Nijmegen, Netherlands.

Titled Proactive and Integrated Management and Empowerment in Parkinson’s Disease (PRIME-PD), the trial will be led by Emily Henderson, MD, geriatrician at the Royal United Hospital and an honorary senior lecturer at the University of Bristol. 

Project partners include The Gatsby Foundation and Radboud University Medical Center in Nijmegen, Netherlands.

“The robust design and evaluation of this new conceptual model will ensure that any positive findings can be widely implemented to ensure that people living with the condition can benefit,” Henderson said.

Project methodology and evaluation will be led by the university’s Bristol Randomised Trials Collaboration (BRTC) and Yoav Ben-Shalom, PhD, professor of clinical epidemiology.

BRTC designs and conducts randomized, controlled trials in patient care settings, as well as in schools and public health fields. It also conducts complex trials and feasibility studies that include methodological research, and provides collaboration and advice for researchers looking to develop and initiate new trials.

While a variety of healthcare providers typically support each Parkinson’s patient, according to the press release, collaboration can be inconsistent. As a result, patients may not get the right services at the right time to deal with disease symptoms.

By way of remedy, the project will craft and test a new model of proactive and cohesive care that hopes to better meet patients’ needs. It will be evaluated both for its ability to improve patient care and cost-effectiveness.

The model will build on the experience and infrastructure already in existence in the United Kingdom and the Netherlands.

 “The only way to overcome the current impasse in healthcare is to have two critical components at your disposal: firstly, adequate funding to cover the gap between the ideal model of care and what is currently reimbursed by national healthcare systems or insurers; and secondly, sufficient amount of time to scientifically demonstrate that the new concept works, as reflected by an improved quality of life for patients as well as cost savings for society,” said Bas Bloem, MD, PhD, professor of movement disorders in the neurology department of Radboud University.

With support from the National Institute for Health Research Clinical Trials Units Support Funding, the BRTC works with clinicians and researchers across the UK. Those interested in working with them may go here for information.

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Source: Parkinson's News Today