Study of the Symptomatic Effects of Nocturnal Sodium Oxybate in Parkinson's Disease
Condition: Sleep-wake Disturbances in Motor-phase Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Sodium Oxybate; Placebo
Intervention type(s): Drug; Drug
Other intervention name(s): Brand name: Xyrem
Intervention MeSH terms: Sodium Oxybate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: excessive daytime sleepiness; Parkinson's Disease; sleep-wake disturbances; Sodium Oxybate