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LRRK2 Mutation and Parkinson's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01424475
Recruitment Status : Terminated (Following extensive efforts to increase recruitment, it will not be possible to complete the study protocol within a reasonable time)
First Posted : August 29, 2011
Last Update Posted : May 11, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE June 23, 2011
First Posted Date  ICMJE August 29, 2011
Last Update Posted Date May 11, 2017
Actual Study Start Date  ICMJE August 11, 2011
Actual Primary Completion Date January 12, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 25, 2011)
  • Imaging (fMRI) [ Time Frame: Day 1 ]
    Action Selection, Tower of London, Shape manipulation, Emotional processing
  • Cognition [ Time Frame: Day 1 ]
    Mini Mental State Examination (MMSE), Reward/punishment learning score, Task-set switching, Attentional set-shifting score, Spatial working memory score
  • Olfactory [ Time Frame: Day 1 ]
    Sniffin' sticks
  • Motor / Other [ Time Frame: Day 1 ]
    Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), Parkinson's Disease Sleep Scale (PDSS), Nonmotor Symptoms Questionnaire, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease, Caffeine/Smoking Questionnaire
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE LRRK2 Mutation and Parkinson's Disease
Official Title  ICMJE LRRK2 Mutation and Parkinson's Disease: A Functional Neuroimaging and Behavioural Study Characterising the Neurocognitive Phenotype
Brief Summary The Leucine-Rich Repeat Kinase 2 (LRRK2) is implicated in autosomal dominant Parkinson's disease (PKD). An inhibitor for the leucine-rich repeat kinase 2 (LRRK2) is in pre-clinical development for potential use in treating Parkinson's disease. Patients with PKD have cognitive impairments which develop alongside the typical motor symptoms but a full characterisation of the neurocognitive phenotype of PKD patients with LRRK2 mutation is currently lacking. This observational study conducted on a single visit will assess the phenotypic neurocognitive abnormalities of PKD patients with the LRRK2 mutation with the aim of identifying potential PD endpoints related to the LRRK2 mutation for future Phase I or II clinical trials of LRRK2 inhibitors.
Detailed Description

The Leucine-Rich Repeat Kinase 2 (LRRK2) is implicated in autosomal dominant Parkinson's disease (PKD). An inhibitor for the leucine-rich repeat kinase 2 (LRRK2) is in pre-clinical development for potential use in treating Parkinson's disease. Patients with PKD have cognitive impairments which develop alongside the typical motor symptoms but a full characterisation of the neurocognitive phenotype of PKD patients with LRRK2 mutation is currently lacking. This observational study conducted on a single visit will assess the phenotypic neurocognitive abnormalities of PKD patients with the LRRK2 mutation with the aim of identifying potential PD endpoints related to the LRRK2 mutation for future Phase I or II clinical trials of LRRK2 inhibitors.

Approximately 20 subjects with PKD bearing one of the known LRRK2 mutations will be investigated. Approximately 20 healthy subjects without the LRRK2 mutation who are matched with PKD patients will also be evaluated.

Healthy subjects are not expected to be taking medications for PKD. Subjects with PKD may continue their medications for PKD treatment throughout the study, Testing will take place within 30 days of screening, depending on the subject's availability.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Parkinson Disease
Intervention  ICMJE
  • Genetic: Healthy
    Healthy Volunteers
  • Genetic: PKD Patients
    PKS Patients
Study Arms  ICMJE
  • PKD Patients
    PKD Patients with LRRK2 mutation
    Intervention: Genetic: PKD Patients
  • Healthy Controls
    Healthy Controls with no LRRK2 mutation
    Intervention: Genetic: Healthy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 14, 2015)
5
Original Estimated Enrollment  ICMJE
 (submitted: August 25, 2011)
40
Actual Study Completion Date  ICMJE January 12, 2015
Actual Primary Completion Date January 12, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Any Subject:

Inclusion Criteria:

  • Male or female, age: >18 years.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • Sufficiently fluent in English that they are able to understand written and spoken instructions in the opinion of the investigator.

Exclusion Criteria:

  • Subjects with previous or current drug or alcohol dependence within 2 years of screening.
  • Subjects who are unable to tolerate study procedures including MRI, or who are unable to perform the study procedures (e.g. due to severe musculoskeletal disease).
  • Use of other prescription or non-prescription centrally acting drugs, including herbal (eg khat) and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the procedures of Day 1, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • Pregnant females as determined by positive serum or urine hCG test at screening.
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  • Subject meets any of the MRI exclusion criteria.
  • Subject is left-handed.

PKD Patients:

Inclusion Criteria:

  • Diagnosis of Parkinson's disease according to the following criteria derived from the UKPD Society brain bank diagnostic criteria for PD (Hughes AJ et al., 1992):

    a) Bradykinesia must be present b) At least one of the following: muscular rigidity Resting tremor postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction c) Supportive prospective positive criteria for Parkinson's Disease (three of the following required for definite diagnosis): Resting tremor unilateral onset progressive disorder in first 5 years following onset, persistent asymmetry affecting side on which symptoms first appeared excellent response (70-100%) to levodopa in the clinical judgement of the investigator, based on the medical notes or during standard care d) None of the following clinical features which suggest a diagnosis other than Parkinson's disease: History of repeated strokes with stepwise symptom progression History of repeated head injury History of definite encephalitis Neuroleptic treatment at symptom onset Sustained remission Strictly unilateral features after 3 years Supranuclear gaze palsy Cerebellar signs In first five years following onset, early severe autonomic involvement such as orthostatic hypotension, impotence and bladder dysfunction Early (within 2 years on symptom onset) severe dementia with disturbed memory, language, praxis Babinski sign CT/MRI scan evidence of tumour or hydrocephalus Negative response to 1000mg of levodopa daily in divided doses.

    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure

  • Parkinson's disease in Hoehn & Yahr criteria Stages I-III.
  • Confirmed ascertainment as having the G2019S mutation in the LRRK2 gene.

Exclusion Criteria:

  • Subjects with clinically significant condition(s) other than Parkinson's disease which, in the opinion of the investigator, would render the subject unsuitable for the study (e.g. psychiatric, haematological, renal, hepatic, endocrinology, neurological [other than Parkinson's disease], cardiovascular, or active malignancy [other than benign skin malignancies]).
  • Subjects with prior or current major psychosis (e.g. schizophrenia or psychotic depression) as assessed by the MINI neuropsychiatric interview.
  • Subjects with severe clinical dementia as measured by UPDRS.
  • Patients who are on centrally acting anti-cholinergic medication that is likely to impair cognitive function.
  • Patients with positive drug screen results may still be included at the discretion of the investigator following a discussion of the result with the subject, and following a discussion with the sponsor.

Healthy Subjects (Controls):

Inclusion Criteria:

  • Matched to patients with LRRK2 mutation for age, gender, premorbid reading IQ, handedness and smoking status (number of cigarettes smoked per day (0-10, 11-20, 21-30 or 30+)).
  • None of the clinical symptoms or signs of Parkinson's disease listed in section 5.2.2.1.
  • No family history of more than one first-degree relative with Parkinson's disease to suggest that the subject may be a carrier of one of the genetic mutations of Parkinson's disease.
  • Confirmed ascertainment as not having LRRK2 mutation.
  • Subject is not a genetically-related family member of a subject with LRRK2 mutation recruited into this study as per criteria above.
  • Subject is healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
  • No current or past history of Axis I psychiatric disorders as determined by MINI interview.

Exclusion Criteria:

  • A positive pre-study drug/alcohol screen.
  • Currently taking any prescription medication, in particular medication with a central mechanism of action, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01424475
Other Study ID Numbers  ICMJE 114500
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP