The Use of the CUE1/CUE1+ in People With Parkinson's Disease and Related Disorders

Not Applicable

Recruiting

• Conditions: Parkinson's Disease and Parkinsonism; Progressive Supranuclear Palsy; Different Types of Tremor Including Essential Tremor; Dystonia; Multiple System Atrophy; Corticobasal Degeneration; Vascular Parkinsonism; Orthostatic Tremor
• Interventions: Device: CUE1 non-invasive device

• Registration Number: NCT06174948
• Lead Sponsor: Queen Mary University of London

Brief Summary

People with Parkinson's disease (PD) commonly experience a range of both motor (e.g., bradykinesia, rigidity, tremor, and postural instability) and non-motor (e.g., fatigue, psychiatric and behavioural disturbances, autonomic dysfunction, cognitive impairment, sleep dysfunction and olfactory loss) features. Currently, it is challenging to alleviate these symptoms with first-line treatment, the medications such as levodopa. The CUE1 is a non-invasive device, which is approved for sale in the UK market as a Class I low risk device. It is worn on the sternum or other part of the body such as the forearm and attaches to the skin via an adhesive patch which has been dermatologically tested and approved.

The CUE1 delivers pulsing cueing and vibrotactile stimulation to help improve symptoms in people with PD and it has shown to be effective in doing so in previous small case studies. This 9-week feasibility study aims to investigate the feasibility, safety, tolerability and effect of using the CUE1 as an intervention to improve motor and non-motor symptoms in people with PD and related movement disorders. People with clinical diagnosis of idiopathic PD and related disorders including those with progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, orthostatic tremor and vascular Parkinsonism as well as atypical dystonias and tremor disorders aged over 18 years old who have the capacity to provide a written consent form to take part in the study, will receive as intervention to wear the CUE1 device at home, on daily basis while carrying out their activities of daily living. Participants will also have to attend face-to-face appointments of approximately half a day, to discuss how they are getting on with using the CUE1 and complete questionnaires on their symptoms, walking, balance, and movement tests as well as a participant's clinical diary.

Detailed Description

Parkinson's disease (PD) may be the fastest growing neurodegenerative disease in the world (Bloem et al., 2021). Pathologically, it is characterised by the loss of the dopaminergic neurons within the substantia nigra pars compacta (SNc) and other pigmented nuclei of the brainstem. At present, the cost of healthcare for the estimated 145,000 people living with PD in the United Kingdom is over £728 million per year rising to a total economic impact of £3.6 billion (Weir et al. 2018). If current projections are correct of people with PD, this will double by 2040 (Dorsey et al. 2018), consequently the figure may exceed £7.2 billion. Most people affected are 60 years or above. However, there are many people who are diagnosed at a younger age. Common clinical manifestations of PD include a range of both motor (e.g., bradykinesia, rigidity, tremor, and postural instability) and non-motor (e.g., fatigue, psychiatric and behavioural disturbances, autonomic dysfunction, cognitive impairment, sleep dysfunction and olfactory loss) features.

The motor features can be present anywhere in the body. Some of the common features are lack of facial expression, low volume speech, stiffness and slowness of movements. Further, gait and balance are often affected. People with PD tend to have a festinating gait, and/or experience postural instability with or without freezing of gait (FOG) which may occur when initiating walking, standing from sitting, turning, and passing through narrow passages or certain circumstances such as approaching a destination (Nutt et al., 2011) or dual tasking (DT) (Bloem et al., 2000; Jacobs et al., 2014; Isaacson et al., 2018). Postural instability, gait problems and FOG may significantly affect a person's ability to perform ADL, increase their falls risk (Muslimovic et al., 2008; Lamont et al., 2017) and reduce their quality of life (QoL). Approximately 70% of people with PD will fall in a year period which can often result in serious consequences including injuries (e.g., fractures and traumatic brain injury) which further increase morbidity, mortality, and healthcare and personal costs (Farombi et al., 2016).

Currently, there is no cure for PD or treatment options available that can slow down the progression of this condition. However, all people with PD are provided options to treat the signs and symptoms of the condition to support their ability to participate in ADL that are meaningful to them (Huber et al., 2011). First line therapy, the dopaminergic medications, have some impact on motor symptoms in PD but rarely get people back to a "normal" state (Killane et al., 2015). People often remain significantly limited in their ADL during 'OFF' state but even during 'ON' state, many features of PD do not respond adequately despite optimal pharmacotherapy (Shukla et al., 2012). Moreover, the usage of medication often has serious side effects, particularly in older adults. The average person living with PD may be taking nine doses of medication a day (Grosset et al., 2007). Thus, drug resistance is another concern and dose limiting side effects is a barrier to successful deployment of pharmacotherapy (Killane et al., 2015). This issue increases with disease progression because neurodegeneration progressively involves non-dopaminergic brain areas. As a result, various non-pharmacological, non-invasive interventions have been developed to manage sensory dysfunction, a major problem in people with PD, associated with PD symptoms (Conte et al., 2013). Cueing and vibrotactile sensory stimulation are two such examples that have been used to modulate sensory dysfunction in people with PD, especially the sensorimotor integration problems.

Cueing is a mechanism of applying an external temporal or spatial stimulus to facilitate movement initiation and continuation and it can be somatosensory, auditory, attentional or visual (Nieuwboer et al., 2007; Muthukrishnan et al., 2019). It is reported to work by shifting habitual motor control to goal directed motor control (Redgrave et al., 2010). Many studies have demonstrated that cueing helps to improve postural control, balance, FOG (van Wegen et al., 2006; Nieuwboer et al., 2007; Munoz-Hellin et al., 2013; Spaulding et al., 2013; Muthukrishnan et al., 2019), as well as DT performance in activities involving the upper (Heremans et al., 2016; Park \& Kim, 2021) and lower (Rochester et al., 2007; 2009; 2010 (a); 2010(b); Fok et al., 2010; Mak et al., 2013; Beck et al., 2015; Chomiak et al., 2017; Mancini et al., 2018; Stuart \& Mancini, 2020) limbs in people with PD. However, many cueing modalities used for the research purposes in the laboratory environments cannot be easily replicated in people's homes. Thus, a recent narrative review recommends the development of cueing wearable systems that can be used at home or in the community to improve gait and posture in PD (Muthukrishnan et al., 2019).

Interventions utilising vibrotactile sensory stimulation in PD can be split into two main groups: a) whole body vibrotactile stimulation and b) focused (e.g., targeted) vibrotactile stimulation. The results on the effectiveness of whole body vibrotactile stimulation on sensory dysfunction and motor symptoms are mixed with a large variation being reported from none to small improvement on motor symptoms, balance, gait and mobility (Dincher et al., 2019). On the other side, focused vibrotactile stimulation which is a non-invasive neuromodulation technique used by somatosensory cues (e.g., tactile/somatosensory cueing) to apply gentle vibrations to focal joints in the body may have a more positive and consistent effect (Basta et al., 2011; Pfeifer et al., 2021). Trials which include cylindrical vibration devices on the triceps (Pereira et al., 2016), a vibrotactile waistband around the abdomen in FOG (Goncalves et al., 2018), vibrotactile insoles to reduce falls (Otis et al., 2016) and a proprioceptive stabiliser on postural instability (Volpe et al., 2014) show promising results. The CUE1 is a non-invasive medical device which utilises a metronome-like pulsed vibration which represents both auditory and somatosensory low frequency cueing and high frequency focused vibrotactile stimulation to help improve motor task performance in people with PD (Tan et al., 2021; Ong et al., 2022; Wilhelm et al., 2022). It is a CE marked and an MHRA registered non-invasive medical device.

Like other cueing and vibrotactile stimulation devices, the CUE1 stands out as a non-invasive medical instrument. It employs a metronome-like pulsed vibration, incorporating both auditory and somatosensory low-frequency cueing, along with high-frequency targeted vibrotactile stimulation. This design aims to enhance motor task performance in individuals with PD (Tan et al., 2021; Ong et al., 2022; Wilhelm et al., 2022). Preliminary assessments of employing the CUE1 indicated an overall enhancement of 16.75% in motor symptoms, as evidenced in the White Paper on Proof of Concept from 2019. This improvement was observed not only in the MDS-UPDRS Part III Motor test score-considered the benchmark for evaluating motor symptoms in individuals with PD-but also in various assessments such as the TUG test, TTT, and diverse gait features, as detailed in the White Papers on Proof of Concept from 2020. Moreover, users reported that donning the CUE1 device contributed to enhanced fatigue levels and increased subjective balance confidence.

Subsequent investigations from smaller-scale studies revealed notable advancements linked to CUE1 usage. Specifically, the device was shown to significantly boost gait speed in the TUG test (Tan et al., 2021) and improve MDS-UPDRS performance scores while reducing falls by an impressive 85% (Ong et al., 2022). Furthermore, a study design acceptance paper authored by Wilhelm et al. in 2022 showcased a reduction in Freezing of Gait (FOG) and an augmentation in walking speed, accompanied by positive feedback from individuals with PD regarding their experience with the CUE1.

This feasibility study will test primarily the feasibility, safety and tolerability and secondary the effect of the CUE1 and the CUE1+ (e.g., updated version of the CUE1 which has better motor and longer battery life but same treatment settings) device in people with PD and related disorders. This clinical study aims to identify whether the results seen in the prototype testing and previous small studies (Tan et al., 2021; Ong et al., 2022; Wilhelm et al., 2022) can be reproduced in a controlled clinical setting. Overall the risk assessment related to the use of the CUE1 and CUE1+ device has been previously tested on people with PD and has shown to have a minimal chance for error or adverse effect to the patient. Based on real world data, the CUE1 has shown to be effective in significantly improving motor symptoms such as rigidity, stiffness, tremor and slowness of movement in people with PD (White Paper-Proof of Concept, 2019; 2020). The CUE1 has also shown to improve fatigue (White Paper-Proof of Concept, 2020), walking speed, balance and FOG and decrease falls in people with PD (Tan et al., 2021; Ong et al., 2022; Wilhelm et al., 2022). The potential harm for the people with PD was very low, the acceptance of using the CUE1 and its renamed/rebranded model with longer battery life and better motor function, the CUE1+ device was very good, and positive user feedback was received (Wilhelm et al., 2022). The device also utilised medical grade established silicone-based skin adhesives. The product is water resistant and designed to CE standards hence product and electrical malfunction risk will be low.

Positive results arising from this feasibility study will strengthen the evidence that the CUE1+ device is feasible to be used, tolerated, safe and help to improve movement and mobility in people living with PD and related disorders. It may also assist in selecting the most appropriate outcome measures to test the effectiveness of the CUE1+ and contribute to the growing academic interest in the application of peripheral stimulation in other neurological disorders with movement, gait and balance problems such as various types of dystonias and tremors, multiple sclerosis, stroke and vestibular disorders.

Study Timeline

• Study First Submitted: 2023-11-30
• Study First Submitted QC: 2023-12-08
• Study First Posted: 2023-12-18
• Study Start: 2024-03-25
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-18
• Last Update Posted: 2024-11-21
• Primary Completion: 2025-03-31
• Study Completion: 2025-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 70

Inclusion Criteria

• Adults over 18 years old
• Clinical diagnosis of idiopathic PD and related disorders including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and vascular Parkinsonism (VaP) as well as atypical dystonias and tremor disorders and Orthostatic Tremor (OT)
• willing to participate and written consent provided after read the participant information sheet.

Exclusion Criteria

Individuals with:

• other neurological disorders excluding idiopathic PD, related disorders such PSP, MSA, CBD, and VaP as well as atypical dystonias and tremor disorders, affecting movement, balance and gait
• metabolic or autoimmune disorders affecting movement, balance and gait
• acute orthopaedic disorders influencing balance control and gait
• audiovestibular disorders including severe hearing loss
• visual disturbances, poor eyesight
• not able to provide written consent form to participate
• clinical diagnosis of cognitive impairment including dementia or Alzheimer's.
• Mental impairments (illusions, hallucinations, impulse control disorders) (self-reported)

Technical contraindications related to CUE1 device:

• implanted metallic or electronic devices usage
• hypersensitivity to vibrotactile stimulation
• skin conditions and/or open wound in the area of where the device will be positioned (e.g., sternum) if taking medicines for PD or related disorder, then on stable dose of treatment for the last three months.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
people with Parkinson's disease and related disorders	CUE1 non-invasive device	Intervention All participants will use the CUE1 device as follows: * during the first two weeks (e.g., 1-2 weeks) of the 9 weeks in the study: once a day for a continuous duration of 2 hours in the morning, 1 hour after taking the medication (if any) for PD or related disorder, every single day; * during the weeks 4-5 of the 9 weeks in the study: once a day for a continuous duration of 8 hours, starting from morning, 1 hour after taking the medication (if any) for PD or related disorder, every single day; * during the weeks 7-8 of the 9 weeks in the study: only at night, through all night, every single night and not during the day at all; Assessments Four face to face appointments will be arranged for each participant. The appointments will take place at week-0 (baseline), week-3 (follow up 1), -6 (follow up 2), and -9 (follow up 3). Each appointment will last approximately half a day.

Primary Outcome Measures

Name	Time	Method
Dropout rate	1 minute	This is a feasibility outcome which will report the dropout rate at each follow up appointment at weeks -3, -6 and -9.
Recruitment rate	1 minute	This is a feasibility outcome, the recruitment rate which will be calculated as the percentage of eligible participants enrolled in the study. This will be reported at each follow up appointment at weeks -3, -6 and -9.
Compliance with interventions	1 minute	This is a feasibility outcome, compliance with interventions, which will be reported as the percentage of days completed using the CUE1 device and duration of using the CUE1 device. These will be reported at each follow up appointment at weeks -3, -6 and -9.
Physical observation	1 minute	This is a safety and tolerability outcome which will be assessed by carrying out a physical observation by research team during the face to face appointments of any adverse event occurring as a result of using the adhesive patches. The adverse events in relation to the CUE1 device will be reported in the participants' clinical diary and discussed during the appointments with the research team.

Secondary Outcome Measures

Name	Time	Method
Patient's Global Impression of Change (PGI-C) questionnaire	5 minutes	There are two parts in the PGI-C questionnaire. In part one, the patient scores on a scale 0-7 (0 = no change or condition has got worse, 7 = a great deal better, and a considerable improvement that has made all the difference) the change in their activity limitations, symptoms, emotions and overall QoL related to painful conditions. In part two, the patient scores on a scale 0-10 (0 = much better, 10 = much worse), the score that matches their degree of change since beginning the specific care (here the intervention with CUE1). The PGI-C will be completed at follow up appointments, at weeks-3, -6, and -9.
Functional Gait Assessment (FGA)	10 minutes	The FGA is a 10-item test that assesses performance on complex gait tasks (i.e., walking with head turns, stepping over an obstacle, stopping and turning or climbing stairs). Scores for each item are between 0-3. The highest score is 30 and greater outcomes are indicative of better performance. The FGA has been validated in healthy people, older adults with a history of falls and balance impairments, and people with balance problems including those with PD. The minimal detectable change for the FGA is reported to be 4 points in people with PD. Scores ≤22/30 identify fall risk and are predictable of falls in community-living older persons within 6 months. In people with PD, the cutoff point for predicting falls is 18/30, with sensitivity of 80.6%, specificity of 80.0%, and positive likelihood ratio of 4.03.
Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Motor Part III	10 minutes	The MDS-UPDRS Motor Part III assesses the motor symptoms in people with PD. There are 33 scores based on 18 questions with several right, left or other body distribution scores. All items have 5 response options with uniform anchors of 0 = normal, 1 = slight (symptoms/signs with sufficiently low frequency or intensity to cause no impact on function), 2 = mild (symptoms/signs of frequency or intensity sufficient to cause a modest impact on function), 3 = moderate (symptoms/signs sufficiently frequent or intense to impact considerably, but not prevent function), and 4 = severe (symptoms/signs that prevent function). Higher scores indicate greater impact of PD symptoms. Score range between 0 and 132, 32 and below is mild, 59 and above is severe.
Participant's clinical diary	15 minutes	This will be completed daily by the participant at home for 9 weeks, starting from week-1 of and finishing at the end of week-9 of the intervention. The diaries will be completed on the weeks of the intervention (e.g., 1-2, 4-5 and 7-8). The research team will provide the same instructions on how to complete the participant's diary to each person during the baseline appointment at week-0.
Timed Up and Go test (TUG)	5 minutes	The TUG assesses mobility, balance, walking ability, and fall risks. The mean time in people with PD has been reported between 10.3-14.8 seconds.
Bradykinesia Akinesia Incoordination test (BRAIN test)	5 minutes	The BRAIN test is used to assess upper limb motor function. The BRAIN test has been redeveloped to run in all internet browser software and has been validated in patients with PD and controls. Participants use the index finger of a single hand to alternately strike the 'S' and ';' keys on a standard computer keyboard, as fast and accurately as possible. The test is repeated for the other hand. The BRAIN test can be accessed at http://www.predictpd.com/braintest and applications to use this can be directed to AJN via the same web link.
Distal Finger Tapping (DFT)	5 minutes	The DFT test is a web-based keyboard tapping test which has been validated to remotely evaluate upper limb movements and quantify separate kinetic components such as speed, akinesia and rhythm as part of motor dysfunction in PD. It is available online via https://predictpd.com/en/braintest, and compatible with regular laptops and computers with a keyboard. The DFT test consists of a 20-second single key tapping test. Participants will be instructed to repeatedly tap the down arrow key with their left index finger, as fast as possible for 20 s, whilst simultaneously depressing the left arrow key with their left middle finger. The same task will then be repeated for the right hand. These instructions stabilise the wrist and forearm, isolating movement to the index finger metacarpal joint, thereby giving a true measurement of distal finger movement.
Activity-specific Balance Confidence (ABC)	5 minutes	The ABC is a 16-item questionnaire which assesses self-perceived balance confidence in daily activities. Scores range from 0-100; scores ≤ 67/100 are associated with increased fall risk. Higher scores indicate greater balance confidence.
Pittsburgh Sleep Quality Index (PSQI)	5 minutes	The PSQI includes seven component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction. Scores range from 0-21 with a higher total score indicating worse sleep quality. In distinguishing good and poor sleepers, a global PSQI score \> 5 yields sensitivity of 89.6% and specificity of 86.5%.
Fatigue Severity Scale (FSS)	5 minutes	The FSS is a 9-item scale which measures the severity of fatigue and its effect on a person's activities and lifestyle in patients with a variety of disorders, including those with PD diagnosis. The items are scored on a 7-point scale with 1 = strongly disagree and 7= strongly agree. The minimum score = 9 and maximum score possible = 63. Higher the score = greater fatigue severity.
Parkinson's Disease Questionnaire (PDQ-39)	5 minutes	The PDQ-39 is a 39-item self-report questionnaire, which assesses PD-specific health related quality over the last month. It assesses how often patients experience difficulties across the 8 quality of life dimensions and impact of PD on specific dimensions of functioning and well-being. The scoring is done on a 5-point ordinal system (e.g., 0 = never, 1 = occasionally, 2 = sometimes, 3 = often, 4 = always). Each dimension's total score ranges from 0 (never have difficulty) to 100 (always have difficulty). Lower scores reflect better quality of life.
Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (Parts I, II, IV).	15 minutes	The rest of the MDS-UPDRS scale consists of three parts (apart from Part III Motor which will be completed already above): Part I, II and IV which include questions to assess non-motor experiences of daily living, motor experiences of daily living, and motor complications, of people living with PD, respectively.
Participant's satisfaction form	5 minutes	This form will be will be provided to participants to complete at the last follow up appointment (week -9) to feedback on their experience on using the intervention, and support and services received from the research team.

Trial Locations

Locations (1)

Queen Mary University of London; 🇬🇧 London, United Kingdom