Trial of Exenatide for Parkinson's Disease
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is a clinical trial in patients with Parkinson's disease, of a drug called
      Exenatide which is already licensed for the treatment of patients with Type 2 Diabetes. There
      have been several groups that have confirmed that Exenatide has beneficial effects on nerve
      cells when tested in the laboratory, that raises the possibility that Exenatide may slow down
      or stop the degenerative process of Parkinson's disease. In an open label trial in patients
      with Parkinson's disease who self administered the drug for 1 year, we have previously shown
      that the drug is well tolerated and shows encouraging effects on the movement and
      non-movement aspects of the disease, even 2 months after patients stopped administering the
      drug. The next step is therefore to formally evaluate whether Exenatide really is a potential
      "neuroprotective" drug, i.e. stops the nerve cells dying in Parkinson's disease, by
      conducting a double blind, placebo controlled trial.
    

Detailed description: 
      This trial aims to generate further data to explore whether 48 weeks exposure to Exenatide
      has an advantage over placebo based on a standard validated assessment of Parkinson's disease
      severity (the MDS UPDRS part 3 motor subscale). This will be measured during the "practically
      defined OFF medication state" i.e. after patients have withheld their conventional PD
      medication overnight. The hypothesis is that Exenatide will be associated with reduced MDS
      UPDRS part 3 scores at the study end.

      To further examine the safety and tolerability of 48 weeks exposure to Exenatide in patients
      with moderate severity PD.

      To collect Pharmacokinetic data regarding the degree of penetration of Exenatide across the
      blood brain barrier. We hypothesise that any central effects of Exenatide will be mediated
      through penetration of Exenatide across the blood brain barrier. Data obtained from rodents
      suggests that blood brain barrier penetration is excellent.

      We propose to use a simple parallel group randomised controlled trial design.

      No double blind data to support the use of Exenatide are currently available therefore
      equipoise exists. The null hypothesis is that Exenatide (as Bydureon) has no effect on
      disease progression.

      Initial identification of potential participants- patients attending their routine follow up
      appointments will be informed about the trial by their neurologist and given a participant
      information sheet.

      Participants who wish to be considered for inclusion in the trial will be screened for
      eligibility at the National Hospital for Neurology and Neurosurgery, according to inclusion
      and exclusion criteria. A narrative of what trial participation entails together with the
      participant information sheet will be used to educate potential participants. Each patient
      will be aware that they have a 50% chance of being allocated active drug or placebo. They
      will confirm their willingness to attend the clinic after an overnight period without their
      conventional PD medication. As part of the informed consent, the contact details of the
      research team will be given to each patient.

      Written informed consent will be obtained from each patient prior to enrollment into the
      trial. All potential patients will be properly informed as to the purposes of the trial and
      the potential risks/ benefits known, or that can be reasonably predicted or expected, by an
      Investigator trained in Good Clinical Practice. The investigator will retain the original
      copy of the Informed Consent Form signed by the patient, a duplicate will be given to the
      patient, and a third copy will be filed in the patient's hospital notes. Only the consent
      form approved by the relevant trial ethics committee will be used.

      Randomisation Eligible consenting patients will be randomly allocated into 2 groups to
      receive either; Bydureon 2mg subcutaneous injection once weekly for 48 weeks n=30, or
      Bydureon placebo subcutaneous injection once weekly for 48 weeks n=30. Randomisation lists
      will be sufficiently long to enable continued randomisation should any patients drop out
      within the first 12 weeks of the study (prior to the first follow up visit).

      Withdrawal of medications All patients will continue to have optimal conventional PD
      medication administered throughout the trial period with the exception of "off medication
      assessments to be performed at 0,12,24,26,48 and 60 weeks.

      Detailed evaluations of all patients will take place at these time points at the National
      Hospital for Neurology & Neurosurgery (NHNN).

      At each assessment the patient will attend the research clinic after an overnight withdrawal
      from their conventional PD medications to allow an objective measurement of their PD
      disability. Patients unable to tolerate being off medication will not undergo randomisation.

      Blood tests will be performed at each visit. At baseline, Blood tests will include full blood
      count, urea and electrolytes, liver function tests, thyroid function tests, glucose, HBA1c,
      amylase and saved serum. At follow up visits, urea and electrolytes, thyroid function, serum
      amylase will be checked and serum will be stored. These samples are to check both safety and
      to allow measurement of Exenatide levels to be performed after trial completion.

      Urine tests A urine sample will be collected at each visit to allow measurement of exenatide
      levels after trial completion.

      A pregnancy test will also be performed for females of child bearing potential at the
      baseline visit.

      Clinical scales Clinical assessments will be performed at each visit using validated scales
      to assess movement and non movement aspects of PD. Vital signs and weight will be measured at
      each visit.

      The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS).

      Part 3 of this scale (motor subscore) will be scored in the absence and presence of
      conventional PD medication. Part 1,2 & 4 of the scale will also be evaluated in the presence
      of conventional PD medication (ON state) to evaluate any change in some of the non-motor
      symptoms of PD, activities of daily living and the complications of chronic PD treatment.

      Unified Dyskinesia Rating scale. This is considered to be the most useful and objective way
      of quantifying dyskinesia severity.

      3 day Hauser diary of PD state (Time- On, Off, Troublesome Dyskinesia, Non-troublesome
      dyskinesia, Asleep). Diary data allows quantification of the amount of time during a 7 day
      period that patients spend in the varying states of movement ability. Patients will bring
      with them diaries to quantify their PD control for the preceding 3 days.

      Mattis Dementia Rating scale (DRS-2). This scale is a validated global measure of cognitive
      ability.

      Montgomery and Asberg Depression Rating Scale (MADRS). This scale allows for physician
      quantification of Depression severity.

      The PDQ39 (Parkinson's disease questionnaire-39). This is the standard disease specific
      measure of quality of life in PD comprising 39 questions. It has been extensively validated
      in previous studies.

      Non-Motor Symptoms (NMS) severity scale. This validated scale is a tool to collect data on
      the frequency and severity of 30 non-motor symptoms sometimes experienced by PD patients.

      EQ5D (a standardised instrument for use as a measure of health outcome). This is a simple 5
      question form and visual analogue scale that allows calculation of quality adjusted life
      years (QALY) to enable health economic analyses to be performed

      Timed motor tests Patients will be asked to perform a Sit-stand-walk timed test and timed
      keyboard taps with left and right hand separately, in both the OFF medication and ON
      medication condition.

      The timed Sit-stand-walk test will incorporate time taken from seated position to stand and
      walk 10 metres, turn and return to original seated position.

      Timed keyboard taps will use online website Braintaptest.com to quantify number of alternate
      taps from key "S" to key ";" using a conventional QWERTY (keyboard layout) keyboard in a 30
      second period with each hand in turn. The software is validated and records number of key
      strokes, dwell time, accuracy & rhythmicity in an automated fashion, is freely available
      online, allows for coded repeatable assessments which are pseudo-anonymised, and date/time
      stamped.

      Lumbar puncture A lumbar puncture will be performed at 12 weeks and 48 weeks to allow
      measurement of exenatide levels after trial completion.

      DaTSCAN A nuclear medicine scan (DaTSCAN) will be performed at baseline and at the final
      visit.

      Teaching injections Patients will be taught how to self administer injections using online
      teaching video with support of trained member of the trial team.

      Concomitant treatments Trial participants will be permitted to use any licensed PD medication
      throughout the course of the trial that is recommended by their referring neurologist.

      Analyses Adverse events will be reviewed at quarterly trial management group (TMG) meetings
      and 6 monthly independent Data Monitoring committee (iDMC) meetings. An interim analysis will
      be performed when the last patient has reached 24 weeks follow up and results presented to
      the iDMC who will make recommendations to the TMG.
    

Intervention name(s): Exenatide; Placebo
Intervention type(s): Drug; Other
Intervention description(s): 2mg, SC (subcutaneous) once weekly. Number of weeks: 48 weeks. Exenatide is a 39-amino-acid peptide; Placebo, 2mg, SC (subcutaneous), once weekly for 48 weeks.
Other intervention name(s): Bydureon
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Parkinson's; Parkinson's Disease; Exenatide; Bydureon