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Molecular Pathology and Neuronal Networks in LRRK2 Parkinson's Disease

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ClinicalTrials.gov Identifier: NCT03782753
Recruitment Status : Not yet recruiting
First Posted : December 20, 2018
Last Update Posted : December 20, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
King's College London

Brief Summary:

Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized clinically by bradykinesia, resting tremor, rigidity, and postural instability. Little is known about the mechanisms underlying neuronal degeneration in PD and currently, no treatment is available to halt disease progression in PD.

The pathophysiological characterisation of phenomena occurring in the time window between the pathological start of the disease and the onset of motor symptoms is crucial to develop potential neuroprotective agents.

Several genes have been discovered providing important insights on the pathogenesis of PD. Mutations of Leucine-rich repeat kinase 2 (LRRK2) are associated with 2-5% of all PD cases in North American Caucasians. LRRK2 is an enzyme that in humans is encoded by the autosomal dominant Parkinson's disease-8 (PARK8) gene, which is associated with an increased risk of PD.

Clinical and digital biomarkers, blood and cerebrospinal fluid (CSF) biomarkers and molecular positron emission tomography (PET) imaging, with specific radioligands, provide invaluable insights to help understand and characterise disease pathophysiology.

The investigators aim to characterize molecular phenomena underlying LRRK2 PD with the hope of providing further insights into possible mechanisms taking place in PD and to help identify targets for disease-modifying therapeutics.


Condition or disease
Parkinson Disease, PARK8 Parkinson Disease Idiopathic Parkinson Disease

Study Type : Observational
Estimated Enrollment : 75 participants
Observational Model: Case-Control
Time Perspective: Other
Official Title: Longitudinal Study of Molecular Pathology and Neuronal Networks in Leucine-rich Repeat Kinase 2 Carriers and Idiopathic Parkinson's Disease Patients and Healthy Controls Using PET, MR Imaging, and Other Markers of in Vivo Pathology
Estimated Study Start Date : December 17, 2018
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2020

Resource links provided by the National Library of Medicine


Group/Cohort
Group A
25 LRRK2-PD patients
Group B
25 idiopathic PD patients
Group C
25 HC subjects



Primary Outcome Measures :
  1. Changes in serotonergic transmission in the ventral and dorsal raphe nuclei, and in raphe projection areas, in LRRK2-PD compared to idiopathic PD. [ Time Frame: One year ]
    The study's main outcome measure is changes in serotonergic neurotransmission within specific brain regions. This will be assessed with positron emission tomography (PET) imaging using the readioligand 11C-labeled 3-amino-4 -(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([11C]DASB).



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Ages Eligible for Study:   30 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
LRRK2 PD patients, idiopathic PD patients and healthy controls.
Criteria

Inclusion Criteria:

All groups

  • Women of child-bearing potential must use protocol-defined contraceptive measures and must have a negative β-hCG test at screening. For sexually active subjects (except females of non-childbearing potential), condoms should be used in addition to other birth control methods during the study, for 15 days after the last dose of investigational drug, and for 3 months after the last administration of PET or SPECT ligands. All male subjects must agree to refrain from donating sperm during the study, for 15 days following the last dose of investigational drug, and for 3 months after the last administration of PET or SPECT ligands. It is important that male subjects not impregnate others while in the study.
  • Adequate visual and auditory acuity to complete the psychological testing.

Idiopathic PD group

  • Clinical diagnosis of Parkinson's disease meeting the Movement Disorder Society Clinical Diagnostic Criteria (i.e. not induced by drugs or other diseases or carriers of PD risk genes such as LRRK2, SNCA, PARK2 etc.).
  • Hoehn and Yahr scale stage 1 or 2.
  • Patients who are drug-naïve (never been treated with dopamine agonists or levodopa) or on dopamine replacement therapy.
  • Patients who have received the diagnosis of idiopathic PD within three years for drug-naïve patients or within eight years for patients on dopamine replacement therapy.

LRRK2 PD group

  • Clinical diagnosis of Parkinson's disease meeting the Movement Disorder Society Clinical Diagnostic Criteria and genetic confirmation of being carriers of LRRK2 PD risk genes, diagnosed after the age of 30 years.
  • Hoehn and Yahr scale stage 1 or 2.
  • Patients who are drug-naïve (never been treated with dopamine agonists or levodopa) or on dopamine replacement therapy.
  • Patients who have received the diagnosis of idiopathic PD within three years for drug-naïve patients or within eight years for patients on dopamine replacement therapy.

Exclusion Criteria:

  • Patients who had previous surgery for PD (including but not limited to deep brain stimulation [DBS] or cell transplantation).
  • Patients who are treated with duodopa or apomorphine.
  • Patients taking serotonin acting drugs such as antidepressants (i.e. tricyclic or selective serotonin reuptake inhibitors etc.)
  • Patients taking drugs acting on SV2A such as antiepileptics (i.e. levetiracetam or brivaracetam etc.)
  • Pregnancy or breastfeeding.
  • Patients with current or a recent history of drug or alcohol abuse/dependence.
  • Patients who have other neurological disorders and known intracranial co-morbidities such as stroke, haemorrhage, space-occupying lesions.
  • Presence of any clinically significant medical condition (including cardiovascular, respiratory, cerebrovascular, hematological, hepatic, renal, gastrointestinal, or other disease) that, based on the judgment of the investigator, is clinically unstable, is likely to deteriorate during the course of the study, could put the patient at risk because of participation in the study, could affect the subject's ability to complete the study, or could influence the study results.
  • History of suicidal behavior or active suicidal ideation.
  • Within 1 year prior to screen or between screen and baseline (Day -1), any of the following: myocardial infarction; hospitalization for congestive heart failure; hospitalization for, or symptoms of, unstable angina; or syncope not related to PD.
  • History or presence of renal disease or impaired renal function.
  • Clinically important infection (e.g., chronic, persistent, or acute infection) within 30 days prior to screen or between screen and baseline (Day -1).
  • History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma of the skin.
  • Clinically significant blood clotting or bleeding disorder, including clinically significant abnormal findings in laboratory assessments of coagulation or hematology.
  • Use of antipsychotic medication within 3 months prior to screen or between screen and baseline (Day -1).
  • Use of any anticoagulant within 30 days prior to baseline PET scan.
  • Use of any oral corticosteroid within 30 days prior to baseline PET scan.
  • Use of metoclopramide within 30 days prior to baseline (Day -1).
  • Use of any thyroid medication within 30 days prior to baseline (Day -1).
  • Regular use (e.g., taken > 3 days/week) of narcotic pain medications within 30 days prior to baseline (Day -1).
  • Presence of any of the following MRI contraindications: pacemaker; cardiac defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; recent coronary or carotid stent; ear implant; CSF shunt; other implanted medical device (e.g., Swan-Ganz catheter, insulin pump); or metal fragments or foreign objects in the eyes, skin, or body.
  • Negative Allen test in both hands, unless the brachial artery is used for arterial cannulation.
  • Claustrophobia and history of back pain that makes prolonged laying on the PET or MRI scanner intolerable.
  • Initiation or change in pharmacologic therapy for symptoms of PD within 30 days prior to screen or between screen and baseline (Day -1).

In addition, the following are exclusionary for subjects participating in CSF sampling:

- Any spinal malformations or other aspects (e.g., tattoos) or other clinical findings (e.g., papilledema seen with ophthalmoscopy) that may complicate or contraindicate lumbar puncture, as judged by the investigator.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03782753


Contacts
Contact: Marios Politis, MD MSc DIC PhD FRCP FEAN +442078485452 marios.politis@kcl.ac.uk
Contact: Gennaro Pagano, MD MSc +442078485755 gennaro.pagano@kcl.ac.uk

Locations
United Kingdom
King's College London Not yet recruiting
London, United Kingdom
Contact: Marios Politis, MD MSc DIC PhD FRCP FEAN       marios.politis@kcl.ac.uk   
Contact: Gennaro Pagano, MD MSc       gennaro.pagano@kcl.ac.uk   
Principal Investigator: Marios Politis, MD MSc DIC PhD FRCP FEAN         
Sponsors and Collaborators
King's College London
GlaxoSmithKline

Responsible Party: King's College London
ClinicalTrials.gov Identifier: NCT03782753     History of Changes
Other Study ID Numbers: 249061
First Posted: December 20, 2018    Key Record Dates
Last Update Posted: December 20, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by King's College London:
Parkinson Disease
LRRK2

Additional relevant MeSH terms:
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases