Assessing the Symptomatic Benefit of Acoustic Slow Wave Enhancement in Parkinson Disease

Assessing the Symptomatic Benefit of Acoustic Slow Wave Enhancement in Parkinson Disease: A Randomized, Double-Blind and Placebo-Controlled Crossover Study

The study is a randomized, double-blind, sham-controlled cross-over trial to assess the efficacy as well as safety and tolerability of auditory SWS enhancement on measured outcomes in Parkinson disease (PD) patients with disturbed nighttime sleep.

Additionally, the investigators will assess the feasibility and efficacy of auditory slow-wave sleep (SWS) enhancement in Mild Cognitive Impairment (MCI) and Huntington Disease (HD) patients in a pilot study.

The study is a randomized, double-blind, sham-controlled cross-over trial to assess the efficacy as well as safety and tolerability of auditory SWS enhancement on measured outcomes in PD patients with disturbed nighttime sleep. Patients will be randomized to 2 groups: Group 1 will first be treated with auditory stimulation for 3 nights and then - after a wash-out period of 4 nights - switched to 3 nights of sham stimulation. Group 2 will first receive sham-stimulation for 3 nights and then switch to 3 nights of auditory stimulation treatment. The wash-out period in between will be 4 nights. Patients and investigators assessing the outcomes will be blinded to the conditions. All interventions will take place at the patients' homes.

The pilot study is aimed at assessment of safety, tolerability, feasibility and efficacy of auditory SWS enhancement on measured outcomes in MCI and HD patients with disturbed nighttime sleep. Patients will be treated with verum or sham auditory stimulation for 2 consecutive nights. All interventions will take place at the patients' homes.

Inclusion Criteria:

• Informed consent as documented by signature
• Diagnosis of PD along international criteria with mild to moderate disease severity (Hoehn- Yahr (HY) stages ll-lll),
• Self-reported sleep problems and subjectively impaired sleep quality (PDSS-2 sleep quality subscale (items 1-3 and 14) ≥7)
• Stable home situation (e.g. long-term place to live) that allows for reliable application of intervention for the duration of the study
• Ability to apply the intervention for the duration of study, either alone or with help of co-habitant
• Sufficient German language comprehension to follow the study procedures and answer all questions related to the study outcomes
• Dosing of dopaminergic and other PD treatment must have been stable for at least 14 days prior to the first intervention period
• Negative pregnancy test during screening (except in women who are surgically sterilized/hysterectomized or post-menopausal for longer than 1 year),
• Age above 18 years

Exclusion Criteria:

• Known presence of neurologic (other than PD), psychiatric, or sleep disorders (others than associated with PD)
• Parkinsonism without response to levodopa; Atypical Parkinsonian syndromes
• Severe medical conditions as renal insufficiency, liver failure or congestive heart failure
• The regular use of benzodiazepines and other central nervous system (CNS)-depressant substances, as well as melatonin and other sleep inducing substances
• Inability to hear the tones produced by the MHSL-SleepBand device
• Absence of slow-wave enhancement by auditory stimulation during the screening night
• Skin disorders/problems/allergies in face/ear area that could worsen with electrode application
• Failure to give informed consent
• Known or suspected drug- or medication abuse
• Known or suspected non-compliance
• Inability to follow the procedures of the study, e.g. due to language problems, cognitive deficits
• Cognitive impairment (Montreal Cognitive Assessment - MoCA <24)
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Previous enrolment in the current study
• Enrolment of the investigator, his/her family members, employees and other dependent persons
• Shift work (work during the night)
• Travelling more than 2 time zones in the last month before intervention starts or during intervention (start of intervention will be adapted to fit with this criteria)
• Substance or alcohol abuse (i.e. > 0.5 l wine or 1 l beer per day)
• High caffeine consumption (> 5 servings/day; including coffee, energy drink)
• Planned medical intervention of substantial relevance, e.g. surgery, during intervention (routine assessments, e.g. check-ups will be allowed)
• Women who are pregnant or breast feeding,
• Intention to become pregnant during the course of the study,
• Lack of safe contraception, defined as: Female patients of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Please note that female patients who are surgically sterilized/hysterectomized or postmenopausal for longer than 1 year are not considered as being of child bearing potential.

Pilot studies:

Inclusion criteria:

• Informed Consent as documented by signature (see Informed Consent Form),
• Age above 18 years
• The diagnosis of MCI along international criteria or manifest HD (diagnosis of HD confirmed by genetic testing, patients above the age of 18 years, manifest HD, diagnostic confidence of 4)
• Stable home situation (e.g. long-term place to live) that allows for reliable application of intervention for the duration of the study,
• Stable regimen of therapeutic drugs for at least 2 weeks prior to the intervention,
• For HD patients: self-ambulatory
• Native German speaker or good understanding of German. Translation assistance will be accepted, if this will allow a nonnative German speaker to comprehensively follow the study protocol including all questionnaires
• Ability to apply the intervention for the duration of study, either alone or with help of co-habitant.

Exclusion criteria:

• MCI: Present diagnosis of neurologic (other than MCI), interfering psychiatric, or severe internal disease
• HD: Diagnosis of juvenile onset HD
• HD: History of co-morbid neurological conditions (e.g. multiple sclerosis or stroke), interfering psychiatric or cognitive disorders
• Severe medical conditions, such as renal insufficiency, liver failure or congestive heart failure
• Inability to hear the tones to be applied during sleep when awake
• Skin disorders/problems/allergies in face/ear area that could worsen with electrode application
• MCI: absence of a cohabitant who could assist with study applications and procedures
• Failure to give informed consent
• Known or suspected drug- or medication abuse
• Inability to follow the procedures of the study, e.g. due to language problems, cognitive deficits,
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Enrolment of the investigator, his/her family members, employees and other dependent persons
• substance or alcohol abuse (i.e. > 0.5 l wine or 1 l beer per day),
• Planned medical intervention of substantial relevance, e.g. surgery, during intervention (routine assessments, e.g. check-ups will be allowed)
• Women who are pregnant or breast feeding,
• Intention to become pregnant during the course of the study,
• Lack of safe contraception, defined as: Female patients of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Please note that female patients who are surgically sterilized/hysterectomized or post-menopausal for longer than 1 year are not considered as being of child bearing potential.