Clinical trial NCT02111122: Study of the Symptomatic Effects of Nocturnal Sodium Oxybate in Parkinson's Disease
Official title: A Phase II, Prospective, Randomized, Double-blind, Crossover Placebo-controlled Study of the Symptomatic Effects of Nocturnal Sodium Oxybate in Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sleep-wake Disturbances in Motor-phase Parkinson's Disease
Keywords: excessive daytime sleepiness
Parkinson's Disease
sleep-wake disturbances
Sodium Oxybate
Lead sponsor: University of Zurich
Sponsor class: OTHER
First posted: 2014-04-10
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Sleep wake disturbance is a common problem in Parkinson's disease patients and so far the therapeutic possibilities for symptomatic relief are limited. Small, open-label studies indicate that the use of Xyrem (gamma-hydroxybutyrate) might be of benefit in this situation.

This study is intended to show a beneficial effect of the study medication in a randomized cross-over trial, that fulfills strict scientific criteria.

Detailed description: Background and Rationale

Non-motor symptoms as excessive daytime sleepiness (EDS) are markedly impairing quality of life in Parkinson's Disease (PD) patients. Beside the disturbing character of these symptoms, EDS for example is also linked to a decrease in cognitive abilities or mood, i.e. depression \[1,2\]. The most prominent cause for EDS is a disruption of nocturnal sleep \[3\]. Furthermore disrupted nocturnal sleep is also likely influencing quality of life of partners or caregivers. This aspect of non-motor symptoms has not been investigated in detail so far. In conclusion, we are firmly convinced that the improvement of nocturnal sleep in PD patients is a promising potential strategy to reduce several symptoms and adverse events in PD patients and their partners or caregivers. Moreover, sleep modulation is a recently introduced approach of potential neuroprotective strategies, e.g. since sleep deprivation was linked with neurodegenerative processes in the brain \[4,5\].

It has already been shown in a recent study that the nocturnal application of sodium oxybate in PD patients is not only improving nocturnal sleep quality, but is accompanied by a reduction in EDS \[6\]. There were, however, significant methodological limitations to this study, since it was a single-arm, open-label, uncontrolled study.

In summary, the nocturnal application of sodium oxybate seems to be a promising treatment for PD patients, but methodologically correct evidence is still lacking.

Investigational Product

The investigational product used in this study is Xyrem, which was approved by Swissmedic in June 2006 for the treatment of cataplexies in patients with narcolepsy. Xyrem belongs to the class of sedatives. The chemical name for sodium oxybate is sodium 4-hydroxybutyrate and its molecular formula is C4H7NaO3. Xyrem oral solution contains 500 mg of sodium oxybate per milliliter of USP Purified Water, neutralized to pH 7.5 with malic acid. It has to be taken orally at night in a split dose regime. It is eliminated mainly by metabolism with a half-life of 0.5 to 1 hour. Pharmacokinetics are nonlinear with blood levels increasing 3.8-fold as dose is doubled from 4.5 to 9 g. The pharmacokinetics are not altered with repeat dosing.

The exact mechanism of Xyrem is unknown. However, Xyrem is enhancing deep sleep and therefore strengthening nocturnal sleep. Since disturbed nocturnal sleep and EDS are major non-motor symptoms in patients suffering from PD we aim to investigate the profit of Xyrem application for PD patients (for detailed information see Arzneimittel-Kompendium der Schweiz 2012).

Clinical Data to Date

An uncontrolled open-label study administered nocturnal sodium oxybate for excessive daytime sleepiness in PD \[6\]. No other tested treatment so far - be it stimulants, be it continuous dopaminergic stimulation overnight - has yielded such a dramatic improvement of EDS: mean Epworth sleepiness scale values dropped down from 15.6 points (severe sleepiness, comparable to patients with narcolepsy) to 9.0 (normal values) (Table 1). In addition, sleep quality and fatigue improved as well.

In terms of safety, the Apnea-Hypopnea-Index (AHI) went up from 7 to 13, but oxygen saturations remained stable on sodium oxybate \[6\]. There were, however, significant methodological limitations to this study. First, it was open-label, and second, excessive daytime sleepiness was assessed only by subjective measures, i.e. with validated questionnaires.

Dose Rationale

The standard maximal dose, corresponding to the maximal dose used in this study, is 9g (corresponds to 18ml) per night in a split dose regime. As Xyrem is approved for long-term use and is only applied over 6 weeks in the current study, no specific precautions concerning the duration of intake has to be done.

The exclusion criteria in the present study meet the contraindications in case of Xyrem application listed by Swissmedic: subjects are not included in case of pregnancy, application of other CNS sedative drugs (opioids, barbiturates), severe medical conditions as liver failure, renal insufficiency, congestive heart failure and severe depression.

As most drugs, Xyrem can potentially and in few cases lead to several adverse events. Since the maximal dose is also accompanied by a higher occurrence of adverse events, the initial dose is set at 3g per night, which is even below the suggested starting dose according to the "Arzneimittelcompendium" and is carefully and stepwise increased to the individual optimal dose carefully. The key feature of a safe application is accurate monitoring of the patients, which is warranted with regular visits and phone calls in the present study.

Xyrem has been associated with potential breathing depression. In the study of Ondo et al. \[6\] total apneas mildly increased after the application of nocturnal sodium oxybate, whereas oxygen de-/saturation values remained stable. Nevertheless, subjects with elevated AHI or low oxygen saturation are not included in the present study (see exclusion criteria section 7.2). However, AHI will be measured before and after drug application in all subjects, allowing a better evaluation of this aspect in the future.

Up to date, there is no approved medication for sleep disturbances or EDS in PD. So far, the application of nocturnal sodium oxybate has revealed the largest improvements in PD patients. Modafinil or Rivotril have been demonstrated to have some benefits on EDS or sleep in PD patients. However, these medications are not really an alternative treatment since the effects are only moderate and the experience of their application in PD patients is still insufficient.

Risk/Benefits and Ethical Considerations

Xyrem is a drug licensed by the FDA and Swissmedic for the use in patients with narcolepsy, and its tolerability in clinical practice is very good. It is known that the use of Xyrem leads to an improvement of the quality of nocturnal sleep in patients suffering from narcolepsy, reducing EDS. In dealing with patients it is well known that sleep disturbances of any kind (endogenous as well as exogenous) impair daytime vigilance and at the same time quality of life. It is known that non-motor symptoms of PD, i.e. EDS, have a major impact on the quality of life of patients - as well as their carers. Improving nocturnal sleep would therefore be a promising possibility to enhance the patients' daytime wellbeing.

In addition to the mentioned symptomatic effect on EDS, sleep modulation might in the future emerge as a potential disease modulating strategy. Experimental animal data have shown an aggravation of neurodegenerative disease with sleep restriction (6) - it is currently under investigation if sleep modulation can work the opposite way as well.

Thereby the controlled risk of the mentioned adverse events in section 4.5 must be seen in relation to the potential benefit of improved quality of life of patients and carers as well as its potential influence on motor and non-motor symptoms and long-term disease modification.

Eligibility criteria: Inclusion Criteria:

* Moderate to severe Parkinson's disease (Hoehn and Yahr II/III) diagnosis according to international criteria \[14\],
* History of disturbed nocturnal sleep and presence of EDS (ESS \>10 points),
* Doses of dopaminergic and other PD treatment must have been stable for at least 14 days prior to the screening visit,
* Negative pregnancy test prior to inclusion (except in women who are surgically sterilized/hysterectomized or post-menopausal for longer than 2 years),
* Patients are capable of giving informed consent,
* Signed Informed Consent after being informed.

Exclusion Criteria:

Atypical Parkinson disorder, Parkinson's disease without response to levodopa,

* AHI \>15 or oxygen saturation consistently below 90% on baseline polysomnography
* diagnosis of sleep apnoea-syndrome or COPD
* Severe dementia (MoCA\<22),
* Moderate to severe depression (HADS\>15).
* Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product,
* Regular use of CNS depressant substances (opioids, barbiturates) as well as melatonin and other sleep-inducing substances,
* Other clinically significant concomitant disease states (e.g., renal insufficiency (creatinin \> 120 resp. GFR \<40ml/min), hepatic dysfunction (GPT \> 100U/l), severe cardiovascular disease, etc),
* Known or suspected non-compliance, substance or alcohol abuse (i.e. \> 0.5 l wine or 1 l beer per day),
* Homeless persons,
* 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 2 years are not considered as being of child bearing potential.

* Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, etc. of the patient,
* Participation in another study with investigational drug within the 30 days preceding and during the present study,
* Previous enrolment into the current study,
* Enrolment of the investigator, his/her family members, employees and other dependent persons,

Primary outcomes:
measure: Objective excessive daytime sleepiness
timeFrame: after 6 weeks of treatment
measure: effect on night-time breathing
timeFrame: after 6 weeks of treatment
Secondary outcomes:
measure: Motor function
timeFrame: after 6 weeks of treatment
measure: Subjective quality of nocturnal sleep
timeFrame: after 6 weeks of treatment
measure: Objective quality of nocturnal sleep including breathing indices
timeFrame: after 6 weeks of treatment
measure: Overall quality of life
timeFrame: after 6 weeks of treatment
measure: Mood
timeFrame: after 6 weeks of treatment
measure: Cognition
timeFrame: after 6 weeks of treatment
measure: Impulse control
timeFrame: after 6 weeks of treatment
measure: Vigilance
timeFrame: after 6 weeks of treatment
measure: Subjective Daytime sleepiness
timeFrame: after 6 weeks of treatment
measure: Sleep wake rhythm
timeFrame: after 6 weeks of treatment
measure: Quality of life for caregivers
timeFrame: after 6 weeks of treatment
Other outcomes:
Locations:
city: Zurich
country: Switzerland
facility: Department of Neurology
Study officials:
affiliation: University of Zurich
name: Christian R Baumann, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buchele F, Hackius M, Schreglmann SR, Omlor W, Werth E, Maric A, Imbach LL, Hagele-Link S, Waldvogel D, Baumann CR. Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2018 Jan 1;75(1):114-118. doi: 10.1001/jamaneurol.2017.3171.