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PKG Wearable Device Objectively Detects Motor Fluctuations, Dyskinesia, Study Shows

PKG motor fluctuations

A wearable motion-tracking device called Personal KinetiGraph (PKG) objectively and effectively assesses Parkinson’s-related motor fluctuations, researchers report.

The study, “The role of Personal KinetiGraphTM fluctuator score in quantifying the progression of motor fluctuations in Parkinson’s disease,” was published in Functional Neurology.

The PKG system, developed by Global Kinetics Corporation, is a wrist-worn movement recording device. It collects data on a person’s motor symptoms, including tremors, slowness of movement (bradykinesia), and abnormal involuntary movements (dyskinesia).

The technology also assesses patients’ motor fluctuations, immobility, and daytime somnolence, or sleepiness. Clinicians also can use it to help study an individual’s likelihood for developing impulsive behaviors, and to collect information on medication compliance.

The device has been cleared by the U.S. Food and Drug Administration, and holds CE certification, meaning it meets EU safety, health, and environmental protection requirements.

Previous studies have shown that PKG is able to distinguish between patients with and without motor fluctuations. Now, investigators at the Cedar-Sinai Medical Center in Los Angeles set up to determine whether the cut-offs of PKG motor fluctuation scores could define the progression of Parkinson’s fluctuation stages.

A total 54 Parkinson’s patients — 37 men and 17 women, mean age of 68 years — used the PKG device for 6 days. The participants then were asked to complete a 2-day standardized motor diary, essentially a journal in which the individuals would self-report and record their motor symptoms.

By applying clinically validated scales and questionnaires, researchers were able to categorize the participants into four groups: non-fluctuators (14 people), or patients without motor fluctuations; early (15 people); moderate (15 people); and troublesome fluctuators (10 people), or individuals with motor fluctuations due to a decline in the usual benefit of levodopa therapy.

Of the 54 individuals who completed the PKG trial, only 39 completed and delivered valid motor diaries. Compliance with the motor diary improved with decreasing severity of motor fluctuations — meaning that patients with less severe fluctuations were more likely to complete the diary.

PKG data revealed the device’s fluctuation scores significantly differentiated early fluctuators and troublesome fluctuators, as well as dyskinetic and non-dyskinetic patients.

Meanwhile, patient-reported motor diaries could not distinguish the four study groups based on the average “off” time, the researchers said.

Dopaminergic medications enable Parkinson’s motor symptom control — meaning that treatment temporarily stops the symptoms. However, as the disease progresses, patients typically need to gradually increase the treatment dose to get the maximum benefit. Even after that, however, they may still experience the reappearance or worsening of symptoms — known as “off periods” — due to the diminishing effects of the therapy.

Average time with dyskinesia, or abnormal involuntary movements, distinguished the non-fluctuators and moderate fluctuators. Importantly, the PKG system identified high dyskinesia scores in patients who denied having it.

“Motor fluctuations, including ‘wearing-off’ and dyskinesia, are associated with increased disease severity and disability, and PD [Parkinson’s disease] patients experience decreased quality of life as their response to medical therapy becomes less predictable,” Echo E. Tan, MD, neurologist at Cedar-Sinai Medical Center and the study’s lead author, said in a press release.

“Effectively managing motor fluctuations is complicated by the lack of objective assessment tools, leading patients and physicians to rely on direct observation in the clinic or patient reports, which may be unrevealing, incomplete and unreliable,” Tan added.

The researchers noted that “wearable devices transcend language barriers, cognitive barriers, as well as time constraints in the clinic.” That makes this wearable device a useful tool to objectively measure motor fluctuations in Parkinson’s disease.

“The results of our study demonstrate that the fluctuation score calculated by the PKG system provides objective quantification of motor fluctuations. This may help improve routine management of PD [Parkinson’s disease] patients and enable more objective assessments in clinical trials of PD [Parkinson’s disease] therapies,” Tan concluded.

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Accordion Pill Can Ease Motor Fluctuations in People with Advanced Disease, Phase 2 Data Show

Accordion Pill trial results

Oral treatment with Accordion Pill-Carbidopa/Levodopa (AP-CD/LD) lessened the variability of levodopa plasma levels and eased motor fluctuations in people with advanced Parkinson’s, according to results of a Phase 2 trial.

The study, “Pharmacokinetics and efficacy of a novel formulation of carbidopa-levodopa (Accordion Pill®) in Parkinson’s disease” appeared in the journal Parkinsonism & Related Disorders. These findings were also presented at the recent 2019 IAPRD World Congress, in Montreal.

Progressive depletion of dopamine levels in the brain results in the hallmark motor symptoms of Parkinson’s. Levodopa is the standard treatment and normally given with carbidopa to ensure delivery to the brain and conversion to dopamine.

People with advanced disease often develop motor fluctuations, characterized by a return of symptoms between levodopa doses due to the drug’s short-term effects. This is associated with levodopa’s limited absorption in the upper part of the gastrointestinal tract.

Intec Pharma’s AP-CD/LD aims to address this problem. The pill has a specific gastric retention and release system with carbidopa and levodopa, which enables release in both immediate and controlled-release modes. Controlled release enables a slow discharge into the stomach over eight to 12 hours, and potentially more steady absorption.

The multicenter, open-label Phase 2 study tested multiple doses of AP-CD/LD – 50/250 mg, 50/375 mg and 50/500 mg — twice per day in more than 60 patients. The treatment’s pharmacokinetics (PK) — its absorption, distribution, and metabolism in the body, and its excretion — and effectiveness were compared to Sinemet, an approved immediate-release (IR) combination (marketed by Merck) which contains 37.5 mg of carbidopa and 150 mg of levodopa.

Results of groups 1 to 4 — out of the six taking part in the trial — showed that all AP-CD/LD doses led to more stable plasma levels of levodopa than Sinemet, and significantly lessened levodopa’s maximum concentration by 57.1% and 66.8% in patients with and without motor fluctuations.

The 50/375 and 50/500 doses significantly reduced motor fluctuations compared to the patients’ current treatment. These doses lowered the mean daily off time — when patients experience tremors and dyskinesia, or involuntary movements — by up to 45% compared to Sinemet.

In turn, the total duration of on time (without dyskinesia) and good on time — without dyskinesia or with non-troublesome dyskinesia — were greater with these AP-CD/LD doses than with Sinemet, as were the proportions of total or good on time during waking hours. Overall, both the duration of off periods and/or on time with troublesome dyskinesia were significantly reduced with both AP-CD/LD doses.

The findings further showed that both these AP/CD-LD doses significantly improved patient and investigator ratings on the Global Clinical Impression scale of Parkinson’s severity.

Treatment-emergent adverse events associated with AP-CD/LD use were in line with the known safety profile of CD/LD formulations. No new safety issues were found throughout the trial.

“AP technology demonstrated effective controlled-release PK performance and reduced motor response fluctuations in advanced [Parkinson’s] patients,” the scientists wrote.

“Importantly, the substantially improved ON time for the AP versus IR [Sinemet] was attained without an emergence of troublesome dyskinesia,” they added.

Intec Pharma is conducting a Phase 3 study in the U.S., Europe and Israel called ACCORDANCE (NCT02605434) that will compare the safety and efficacy of AP-CD/LD and Sinemet in 462 adults with advanced Parkinson’s. Two different AP-CD/LD doses are being tested — 50 mg of carbidopa with 400 or 500 mg of levodopa, two or three times a day.

As these doses generally match those used in the Phase 2 study, the investigators expect “similar stable LD and CD plasma levels within the therapeutic range necessary for [Parkinson’s} symptom control.” Topline results are reported as likely to be released this summer.

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Final Visit Completed for Last Patient in Phase 3 Trial Testing Accordion Pill

Accordian Pill trial

The last Parkinson’s patient in Intec Pharma’s Phase 3 ACCORDANCE clinical trial has completed their final visit, the company announced.

Taking place at approximately 90 clinical sites throughout the United States, Europe, and Israel, the trial (NCT02605434) was designed to test the safety and efficacy of the Accordion Pill-Carbidopa/Levodopa (AP-CD/LD) compared with immediate release Sinemet, an approved combination of levodopa and carbidopa marketed by Merck, and with placebo in the treatment of advanced Parkinson’s disease.

“We are excited to announce that the last patient’s last visit has taken place as it is an important milestone in the development of our Accordion Pill platform. Completion of the ACCORDANCE study brings us closer to potentially providing an enhanced baseline levodopa treatment to advanced [Parkinson’s disease] patients,” R. Michael Gendreau, MD, PhD, chief medical officer of Intec Pharma, said in a press release.

The Accordion Pill is an innovative drug delivery system that helps release the commonly used Parkinson’s therapy carbidopa/levodopa slowly in the stomach over hours. This new system allows the therapy to be released in both immediate- and controlled-release modes.

Controlled release enables a slow discharge of the therapy in the stomach over eight to 12 hours, potentially allowing for more steady absorption in the upper gastrointestinal tract, where levodopa is absorbed.

“By delivering more uniform levodopa plasma concentrations than those provided by currently available orally-administered levodopa products, we expect to improve the duration and consistency of symptom relief provided by levodopa. Assuming successful ACCORDANCE study outcomes, we believe the AP-CD/LD will result in improved motor fluctuation control, reduced symptomology, a simpler dosing regimen and enhanced compliance,” Gendreau said.

Prior to the 13-week randomized part of the study, 462 patients were first stabilized and optimized on Sinemet and then on AP-CD/LD during two open-label periods lasting six weeks.

Then, 320 of these patients were randomized to receive either an AP-CD/LD capsule — containing 50 mg of carbidopa with 400 or 500 mg of levodopa — two or three times a day and a matching Sinemet placebo. Or they were given an immediate-release Sinemet tablet — consisting of 25 mg of carbidopa and 100 mg of levodopa — and a matching AP-CD/LD placebo at least four times a day.

The study’s primary goal is the reduction in the percentage of daily “off” time during waking hours (based on patients’ home diaries), which will be considered statistically significant if it leads to at least a one-hour difference between Sinemet and AP-CD/LD. Off time refers to motor fluctuations when levodopa wears off and Parkinson’s symptoms return.

Secondary goals include the reduction of involuntary movements during “on” periods, and improvement in Clinical Global Impression Scale-Improvement (CGI-I) scores — as recorded by the physician and patient — and the Unified Parkinson’s Disease Rating Scale (UPDRS), which assesses both motor and non-motor symptoms.

To date, a preliminary analysis of the initial clinical data shows that the average age of participants at study enrollment was 63 years (66% males); patients have had a diagnosis of Parkinson’s for an average of 8.7 years; and the average daily off time for the group given Sinemet was approximately five hours.

All participants completing the 13-week randomized period were eligible to enter an open-label extension study where they all receive AP-CD/LD for an additional 12 months. More than 90% of eligible patients have chosen to continue in the extension study.

Clinical data and patient diaries are in the process of being validated, and results are expected to be announced this summer.

“With topline results expected this summer, we are actively making plans for our regulatory submissions. Toward that end, we are encouraged that more than 90% of eligible patients elected to enroll in the AP-CD/LD long-term open-label extension (OLE) study as these data will provide the long-term safety required as part of the registration package. In addition, we have made significant progress with our commercial scale manufacturing plans and expect to initiate the validation, bridging and stability studies in the coming months,” said Jeffrey A. Meckler, CEO of Intec Pharma.

“We look forward to receiving the results from the ACCORDANCE trial and, if successful, having them confirm that treatment with AP-CD/LD reduces motor complications in advanced PD patients in comparison to treatment with standard oral levodopa,” he added.

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#AANAM – Opicapone Can Prolong ‘On-Time’ Levopoda Provides, Data from Phase 3 Trials Show

Opicapone add-on therapy

Once-daily opicapone can prolong the time during which treatment with levopoda, a standard therapy, effectively prevents motor symptom fluctuations in people with Parkinson’s disease, results from two international Phase 3 studies show.

The findings, “Once-Daily Opicapone Increases ON-Time in Patients with Parkinson’s Disease: Results from Two Phase 3 Studies,” were presented during the 2019 Annual Meeting of the American Academy of Neurology (AAN), now underway in Philadelphia.

Opicapone, developed by Bial and Neurocrine Biosciences, is designed as a once-a-day add-on therapy to levodopa for adults with Parkinson’s and end-of-dose motor fluctuations.

It works as an inhibitor (blocker) of the enzyme catechol-o-methyltransferase, or COMT, which breaks down levodopa. This can  prolong levodopa effects, known as “on-time” or “on-periods,” as it lessens the time when the medication wears off before the next dose — so-called “off periods.”

Opicapone is marketed in Europe under the brand name Ongentys, and approved for patients with fluctuations that cannot be treated with lepodova or combinations of similar therapies, and whose motor symptoms re-emerge before the next dose is due.

Neurosciences, which holds a North American license for it, has announced plans to submit an approval request for this potential treatment to the U.S. Food and Drug Administration (FDA) this year.

Potential benefits of opicapone were assessed in two Phase 3 trials, BIPARK-1 (NCT01568073) and BIPARK-2 (NCT01227655). The trials enrolled more than 800 Parkinson’s patients who could not effectively control their motor symptoms with standard therapies. They were randomly assigned to receive 5, 25, or 50 mg daily doses of opicapone, plus either levodopa, Comtan (entacapone, sold by Novartis), or a placebo.

After 14 to 15 weeks of treatment, patients had the opportunity to continue opicapone add-on therapy for more than one year in an open-label extension study.

Data from the BIPARK-1 trial showed that people treated with 50 mg opicapone experienced about twice longer on-time periods without dyskinesia (involuntary movements) compared to those given a placebo. (Ongentys is available in Europe as 25 mg and 50 mg capsules; the higher dose is the recommended bedtime dose.)

Similar results were reported in the BIPARK-2 study, in which patients taking 50 mg of opicapone had 1.7 hours of absolute on-time without dyskinesia compared to 0.9 hours in the placebo group.

Longer on-time periods were also observed in long-term extension studies in all opicapone-treated patients, with increases of 2 and 1.8 hours in the BIPARK-1 and BIPARK-2 trials, respectively, the presentation data also show.

In terms of safety, pooled data from the two studies found that more patients in the opicapone-treated group experienced common dyskinesia that was linked to the treatment, compared to those in the placebo arm (17.4% vs 6.2%, respectively). But reported incidences of severe or serious dyskinesia were low, and few from either group withdrew from the studies.

“Once-daily opicapone increased ON-time without troublesome dyskinesia in Parkinson’s disease patients with motor fluctuations,” the researchers wrote.

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First Patient Dosed with VY-AADC Gene Therapy in Parkinson’s Phase 2 Trial

RESTORE-1 Voyager VY-AADC

Voyager Therapeutics has begun patient dosing in a Phase 2 trial testing its investigational VY-AADC gene therapy in Parkinson’s patients whose motor symptoms are not responding adequately to oral medication.

The trial, called RESTORE-1 (NCT03562494), is recruiting participants across seven sites in the United States.

VY-AADC is a therapy that delivers the DDC gene, which provides instructions for making the AADC enzyme, directly to brain cells in the putamen region. The enzyme converts the standard-of-care Parkinson’s treatment levodopa into dopamine, the signaling molecule that is lacking in Parkinson’s disease.

The approach is expected to bypass the effects of degenerating dopamine neurons in the substantia nigra, a part of the midbrain, by increasing dopamine levels in the putamen.

In an ongoing Phase 1b trial (NCT01973543), a single administration of the therapy induced robust and durable improvements in patients’ motor function up to three years after treatment.

The treatment also effectively increased AADC enzyme activity, allowing patients to reduce their doses of oral levodopa. Also, patients reported significant improvement in quality of life.

The newly begun Phase 2 trial aims to determine whether VY-AADC is better than a placebo at reducing motor fluctuations in Parkinson’s patients whose symptoms are not effectively controlled with levodopa or related treatments.

The trial is expected to enroll approximately 42 patients who have been diagnosed with Parkinson’s disease for at least four years and are not responding adequately to oral medications. To be eligible, participants must be experiencing at least three hours of OFF time during the day, as measured by a validated, self-reported patient diary.

Participants will be randomized to receive either a single infusion of VY-AADC or a placebo into the brain via surgery. They will be followed for 12 months to determine their changes in motor fluctuations, changes in the ability to perform daily activities, and quality of life.

During the new Phase 2 trial, researchers will also determine the efficacy of treatment delivery by assessing AADC enzyme levels and activity in the putamen through positron emission tomography (PET). Changes in patients’ daily doses of oral levodopa and related medications will also be evaluated.

More information about RESTORE-1, including recruitment details, can be found here.

“Patients with Parkinson’s disease need new therapeutic options, especially as the disease progresses and there is less AADC enzyme in parts of the brain where it is needed to convert levodopa to dopamine,” Mark Richardson, MD, PhD, associate professor, director of Epilepsy and Movement Disorders Surgery at the University of Pittsburgh Medical Center and principal investigator in the RESTORE-1 trial, said in a press release.

The U.S. Food and Drug Administration granted regenerative medicine advanced therapy (RMAT) designation to VY-AADC for therapy-resistant motor fluctuations in Parkinson’s patients.

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24-hour Levodopa-carbidopa Intestinal Gel Lessened Dyskinesia, Parkinson’s Study Finds

dyskinesia, levodopa-carbidopa intestinal gel

A 24-hour treatment with a levodopa-carbidopa intestinal gel (LCIG) lessened the duration and functional effect of dyskinesia — involuntary, jerky movements — in Parkinson’s patients, according to a small study.

The research, “24-hour levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson’s disease,” was published in npj Parkinson’s disease.

Continuous intra-jejunal (the middle part of the small intestine) infusion with a LCIG has been shown to efficiently treat Parkinson’s motor fluctuations. The gel normally is administered with a portable pump directly into the duodenum or upper jejunum by a permanent tube inserted surgically.

Currently, it is mainly used as a 16-hour per day continuous infusion, and is licensed for use in this way. However, additional benefits have been observed when used as a continuous 24-hour infusion in the treatment of severe nocturnal akinesia (losing the ability to move muscles voluntarily), daytime falls and freezing of gait (FOG), as well as poor sleep quality.

Clinical trials have shown that a 16-hour treatment with LCIG can effectively reduce levodopa-induced dyskinesia (LID), which typically occurs after long-term therapy, despite an increase in daily levodopa dose. Current treatments options for LID, such as deep brain stimulation and Gocovri (amantadine, by Adamas Pharmaceuticals) are not uniformly available or are not suitable for all patients.

Researchers from Movement Disorder Unit at Westmead Hospital, in Australia, have now described their clinical experience with a 24-hour LCIG infusion to treat dyskinesia in Parkinson’s patients.

Of 74 patients treated with LCIG for motor fluctuations, 12 (10 men) were treated with 24-hour daily infusion intended to control troublesome daytime dyskinesia and with sufficient data pre- and post- initiation of continuous treatment. Patients’ mean age at the start of 24-hour LCIG was 69 years and mean duration of Parkinson’s was 18 years. Two had a mutation in the PRKN gene, whose mutations are associated with the juvenile form of Parkinson disease.

Among these 12 patients, four took 24-hour LCIG infusion due to lack of response to 16-hour therapy; two due to troublesome dyskinesia and levodopa-unresponsive FOG; three due to levodopa-unresponsive FOG with non-troublesome dyskinesia; two more had troublesome dyskinesia and nocturnal akinesia; and one self-initiated 24-hour therapy. Two transitioned from oral levodopa, without an in-between 16-hour infusion.

Patients’ clinical characteristics, as well as dyskinesia severity and incidence, were analyzed before and after therapy using the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) – part 3, part 4 (motor complications) total scores and sub-scores 4.1 (time spent with dyskinesias) and 4.2 (functional impact of dyskinesias). All evaluations were performed at baseline and at six months after starting 16- and 24-hour LCIG.

Daytime dyskinesia was reduced in nine patients (75%) following 24-hour therapy, including seven who were first treated with 16-hour infusion and the two patients who transitioned from oral levodopa.

Of the three patients without decrease in dyskinesia, one could not tolerate 24-hour infusion due to worsening of hallucinations and agitation, and shifted back to 16-hour therapy after two months. After six months, the patient’s neurocognitive function returned to baseline. A second 24-hour therapy was initiated 11 months later, but again led to no benefit. The remaining two patients had no change in dyskinesia despite eased FOG and nocturnal akinesia.

Combining the results from all 12 patients, both the time spent with dyskinesia and its functional impact were reduced during 24-hour LCIG treatment. In contrast, the MDS-UPDRS part 3 “ON” scores — control of motor symptoms — did not change.

Five patients showed lessened dyskinesia despite an overall increase in the total daily levodopa dose. No patient had worsened dyskinesia after a median follow-up of 27.5 months.

A total of three patients had worsening of nocturnal hallucinations, which diminished after lowering the night-time LCIG continuous rate. One patient developed asymptomatic peripheral neuropathy (nerve damage) within six months of 24-hour therapy, which remained stable during 18 months of follow-up.

Ten patients experienced vitamin B6 deficiency requiring supplementation, while seven developed vitamin B12 deficiency during therapy (16- or 24-hour). Two patients had hyperhomocysteinaemia (excess blood level of homocysteine), a condition associated with cardiovascular problems and neuropathy.

Of note, no patient elected to return to 16-hour infusion due to difficulty managing the pump, or technical difficulties with the jejunal tube.

Overall, if future studies confirm these findings, “24-[hour] LCIG may offer a novel approach to the treatment of troublesome dyskinesias which persist despite an adequate trial of 16-[hour] therapy,” researchers wrote.

Although further research is necessary to assess the mechanisms involved, the researchers hypothesized that the benefits with 24-hour treatment in patients not responding to 16-hour infusion may be due to continuous levodopa delivery to the brain.

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Non-Motor Symptoms During Wearing-off Periods Associated with Worse Quality of Life in Parkinson’s Patients

Parkinson’s patients with non-motor symptoms during “wearing-off” periods — when symptoms return as their medication wears off — have a significantly worse quality of life compared to patients who only experience the return of motor symptoms, a new study shows.
The study, “Motor and non-motor wearing-off and its impact in the quality of life of patients with Parkinson’s disease,” was published in the journal Arquivos de Neuro-Psiquiatria.
Motor fluctuations refer to the alterations between periods of being “on,” during which a Parkinson’s patient experiences a positive response to medication (generally levodopa), and being “off,” during which the medication wears off and symptoms return.
“Off” periods are more common as the disease progresses and people take medication for a longer period of time.
Motor fluctuations in patients with Parkinson’s disease have been studied extensively. But little is known about non-motor symptoms during “on” and “off” periods.
Motor wearing-off includes the re-emergence of motor symptoms such as tremor, rigidity, and bradykinesia (slowness of movement). Non-motor symptoms include anxiety, fatigue, and depression.
Non-motor symptoms have a significant impact on a patient’s quality of life, as the burden can often be more disabling compared to motor symptoms.
Researchers have developed tools to assess wearing-off in Parkinson’s patients. In particular, the wearing-off questionnaire (WOQ-19) has been used in studies as a screening tool to identify which patients experience the wearing-off phenomena.
The team conducted a cross-sectional study to assess the impact of motor and non-motor wearing-off on daily activities and quality of life in Parkinson’s patients. All patients were evaluated using the movement disorders society unified Parkinson’s disease rating scale (MDS-UPDRS, to follow disease progression), the WOQ-19, and the Parkinson’s disease questionnaire-8 (PDQ-8) to assess quality of life.
Among the 271 patients included, 73.4% had wearing-off. Researchers then classified those patients according to the type: 63.8% had mixed wearing-off (motor and non-motor), 32.7% motor, and 3.5% non-motor.
As expected, the MDS-UPDRS part I total score — which assesses non-motor aspects of daily living — was higher (worse) in the non-motor wearing-off group. Interestingly, there were no differences in MDS-UPDRS part I score between patients in the mixed wearing-off group and those who did not experience wearing off.
“This finding suggests that patients with motor wearing-off may have a lower overall burden of non-motor symptoms, while patients with mixed or no wearing-off have similar burdens,” researchers said. “Conversely, patients with non-motor fluctuations also have a higher burden of non-motor symptoms.”
Parkinson’s patients in the non-motor wearing-off group also had the worst score in the PDQ-8, followed by patients in the mixed wearing-off group. On the other hand, patients with no wearing-off and those with only motor wearing-off had a better quality of life.
“[T]he present study shows that both motor and non-motor fluctuations have an impact on activities of daily living and quality of life. However, the presence of non-motor fluctuations did significantly worsen the quality of life,” the authors wrote.
“The identification and assessment of non-motor fluctuations in the day-to-day clinical practice could result in the improvement of the quality of life of patients with [Parkinson’s disease],” the team concluded.
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Study Outlines Risk Factors for Frequent Falls in Parkinson’s Patients

frequent falls risk

Motor fluctuations, treatment with antidepressants, disease severity, and deep brain stimulation (DBS) are among the risk factors that contribute to frequent falls in patients with Parkinson’s, a large-scale study reports.

According to researchers, identifying predictors that put Parkinson’s patients at the greatest risk for falls can aid in early intervention to prevent these occurrences.

The study, “What predicts falls in Parkinson disease?” appeared in the journal Neurology: Clinical Practice.

Parkinson’s patients may experience falls as a result of their motor symptoms, such as uncontrollable accelerations, impaired balance, and freezing of gait. Approximately 50 percent of these falls require medical care.

Although a history of falling is considered the major risk factor for future falls, research reported that even individuals without any previous occurrences had a considerable risk of future falls. Other risk factors include disease stage and duration, older age, absence of tremor at rest, severity of motor impairment, cognitive dysfunction, taking antidepressants, and DBS — a surgical procedure to treat motor symptoms in Parkinson’s.

Recent studies also pinpointed dopaminergic treatment — intended to restore the reduced level of the neurotransmitter dopamine in Parkinson’s patients — disease severity, and gait characteristics, as well as clinical tests, as predictors of falls among patients without any previous history.

Researchers in this study analyzed longitudinal data from the National Parkinson Foundation Quality Improvement Initiative (NPF-QII) registry (NCT01629043) to discover what factors set apart Parkinson’s patients who are most likely to become frequent fallers.

The study included 3,795 participants from 19 NPF Centers of Excellence. A total of 3,276 (86.3%) patients reported no or rare falls in the three months prior to the first visit, of which 382 (11.7%) became frequent fallers by the annual follow-up visit. This rate is similar to those reported in prior studies, the researchers noted.

Predictors of falls included motor fluctuations, treatment with levodopa and antidepressants, DBS, reduced health-related quality of life, less than 90% of Parkinson’s diagnostic certainty, female sex, and worse semantic fluency (part of verbal fluency).

Another risk factor for falls was being a stage 2 or 3 on the Hoehn and Yahr scale — which is used to describe the progression of Parkinson’s symptoms, where stage 2 refers to bilateral involvement without impaired balance, and 3 to mild to moderate bilateral disease with postural instability but physical independence.

Regarding the association with antidepressants, the investigators said that although they are a known risk factor for falls in older adults and could indicate a greater incidence of depression — also a risk factor — clinicians should consider nonpharmacological alternatives to treat depression in Parkinson’s patients at risk of falling.

Between visits, factors contributing to conversion to “frequent faller status” included the addition of amantadine for involuntary muscle movements, a referral to occupational therapy, diagnoses of cancer or osteoarthritis, newly implemented DBS, and an increased need for social and hospital services, including more emergency visits, which may indicate poorer global health, the researchers said.

As for the correlation between DBS and the risk of falling, according to the authors, this finding is in line with evidence showing that postural instability and falls may worsen within the first year after surgery.

“We have identified a number of associations between disease characteristics, treatments, and comorbidities and emergent falls in [Parkinson’s],” they wrote. “Such identifiers may help target patient subgroups for falls prevention intervention.”

However, the scientists cautioned that although the analysis provides associations between risk factors and falls in Parkinson’s patients, it does not prove causality.

The NPF-QII registry is still recruiting participants for an estimated total of 10,000. It aims to identify the best expert care practices for improved outcomes, including survival and quality of life. The study is being conducted across the U.S., Canada, and in the Netherlands and Israel. More details on locations and contacts can be found here.

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Sunovion’s Below-the-Tongue Therapy Eases Parkinson’s Movement Difficulties, Trial Shows

Below-the-tongue therapy

Sunovion Pharmaceuticals’ below-the-tongue version of a Parkinson’s therapy was able to ease patients’ movement difficulties after the standard therapy levodopa wore off, a Phase 3 clinical trial showed.

Patients also tolerated the treatment — known as apomorphine sublingual film — well, the preliminary results showed. Sublingual means below the tongue, so the therapy’s full name refers to an apomorphine film placed below the tongue. The only approved version of the drug at the moment is administered by injection.

Parkinson’s symptoms stem from a drop in the brain’s levels of the neurotransmitter dopamine, which controls movement. Apomorphine, also known as APL-130277, works by mimicking dopamine’s activity in the brain.

Between 40 and 60 percent of Parkinson’s patients have ups and downs in their ability to control their movement. When they are responding well to a standard medication — that is, they are in an on period — they do all right. When their drug is losing its punch— or in an off period — they don’t do as well.

In an off period, patients can walk slowly, experience tremors and stiffness, and have trouble getting around. There are several types of off periods. One occurs only in the morning. Another occurs when a treatment is wearing off. And it’s impossible to predict when some off periods will occur.

Taking an oral medication is easier than other ways, so it’s the option most Parkinson’s patients prefer. But many have difficulty swallowing. Sunovion developed an under-the-tongue version of apomorphine to get around the problem of an oral version that needed to be swallowed.

“If an alternative method to deliver the medicine were approved, such as apomorphine sublingual film, it would be an important new option for healthcare providers and people with Parkinson’s disease,” Stewart Factor, the principal investigator of the Phase 3 study, said in a press release. He is chief of neurology at Emory University School of Medicine.

In the Phase 3 CTH-300 trial (NCT02469090), researchers randomly assigned 219 participants to receive apomorphine sublingual film or a placebo. The patients had been responding to the levodopa they were taking but experiencing at least one off episode per day. Their cumulative off time was at  least two hours a day.

The study’s primary goal was to see at week 12 if under-the-tongue apomorphine could improve patients’ movement within 30 minutes. A secondary objective was to identify the percentage of patients reporting a full on response within 30 minutes of treatment.

Preliminary results showed that the 109 apomorphine-film-treated patients were able to reduce their movement problems more than the placebo group within 30 minutes of putting the film under their tongue.

The therapy was still working 90 minutes after treatment, researchers. Patients tolerated it well, they said.

At week 12, more apomorphine-film-treated patients were experiencing a full on response within 30 minutes of dosing than the control group.

“For people with Parkinson’s disease and their families, OFF episodes can have a significant emotional and practical impact, and there are currently few treatment options for these events,” said Antony Loebel, the executive vice president and chief medical officer of Sunovion. “Based on these topline results, we believe that apomorphine sublingual film has the potential to be a well-tolerated, reliable, convenient and fast-acting therapeutic option for people living with Parkinson’s disease who struggle with OFF episodes.”

Sunovion plans to use the full trial results to support its New Drug Application in the United States for apomorphine sublingual film as a Parkinson’s therapy. The U.S. Food and Drug Administration has already granted it Fast Track Designation, a status aimed at accelerating its regulatory review.

The post Sunovion’s Below-the-Tongue Therapy Eases Parkinson’s Movement Difficulties, Trial Shows appeared first on Parkinson’s News Today.

Source: Parkinson's News Today