Parkinson DiseaseNCT04349865
LRRK2 Activity and Markers of Parkinson's Disease in G2385R Carriers
An observational study of Parkinson Disease, run by Xuanwu Hospital, Beijing at 1 site in China.
Trial summary
The goals of this study are 1. To compare the functional effects of the LRRK2 G2385R variant among carriers with and without Parkinson's disease (PD) and non-carriers with and without PD 2. To investigate the relationship between functional effects of the LRRK2 G2385R variant and PD associated phenotype 3. Read more about this study
- Who is it for?
- Ages 55 years and olderHealthy volunteers can take part
- Conditions the study is for
- Parkinson Disease
- How many people
- 211 participants
- Where
- 1 siteChina
- Study dates
- 22 May 2018to 25 Dec 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: (1) PD patients are from the Chinese National Consortium of Parkinson Disease (CNCPD) cohort; meanwhile, new patients are enrolled from outpatient and inpatient departments. 2) Unaffected subjects are from a large population-based cohort (the Beijing Longitudinal Study of Aging).
Who may be able to join
- PD patients:
- A diagnosis of Parkinson's disease according to the 2015 MDS PD diagnostic criteria.
- Willingness to take genetic testing.
- Unaffected subjects:
- Individuals aged 55 years or older without a diagnosis of PD.
- Willingness to take genetic testing.
Who cannot join
- □ Clinically significant neurological disorders.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Assessment of LRRK2 Activity in G2385R Carriers and Markers Predicting Conversion to and Progression of Parkinson's Disease
The goals of this study are
- To compare the functional effects of the LRRK2 G2385R variant among carriers with and without Parkinson's disease (PD) and non-carriers with and without PD
- To investigate the relationship between functional effects of the LRRK2 G2385R variant and PD associated phenotype
- To investigate the biomarkers associated with PD conversion in the LRRK2 G2385R variant carriers
- To compare the immune-related differences between PD patients/unaffected individuals with and without the LRRK2 G2385R mutation, and to investigate the effects of immune dysfunction on the clinical expression of PD
Read the detailed description
Pharmaceutical companies with LRRK2 kinase inhibitor programs are close to Phase 1 clinical testing. Phase II proof-of-concept clinical trials will need to be conducted in LRRK2 manifesting mutation carriers. This is currently a challenging task given the limited availability of this cohort.
While the LRRK2 G2019S mutation is the most common mutation present in Caucasians and certain ethic groups, the G2385R variant has been identified as a risk factor for sporadic PD in the Asian population (Chinese Han, Japanese and Korean). In fact, in these populations, the occurrence of this mutation is thought to be higher than (up to 4% of PD patients) the occurrence of the G2019S mutation in the Caucasian population. In contrast to G2019S, this variant has not been fully characterized. For example, there has been controversy regarding its kinase activity with some reporting higher and others lower activity. A systematic biochemical characterization of the G2385R is necessary to determine if this cohort may be useful in LRRK2 kinase inhibitor trials.
Although there were significant studies on the clinical characterization of LRRK2 risk variant carriers with or without PD, little is known which factor is more specific in predicting the conversion to PD and which biomarker can be used to measure the disease progression. Identifying these clinical phenotype and biomarkers will be critical for studying pharmaceuticals effective for PD.
Several lines of evidence point to a role of LRRK2 in the immune system. Particularly high LRRK2 expression has been discovered in macrophagic and monocytic cells, but not T-cells, leading to speculation of a functional role for LRRK2 in the innate immune system. LRRK2 is also expressed in toll-like receptor 4 (TLR-4)-activated microglia, brain-resident macrophage cells that have been implicated in the pathology of PD brain, and LRRK2 modulates proinflammatory responses in these cells via several immune signaling pathways. Moreover, enhanced neuroinflammation may contribute to neurodegeneration in PD patients carrying LRRK2 mutations. Further, recent genome-wide association studies highlight LRRK2 in the modification of susceptibility to the chronic autoimmune Crohn's disease and Mycobacterium leprae infection, raising the possibility that LRRK2 may contribute to PD through immunogenic mechanisms. Although neuroinflammation as a primary trigger or secondary process linked to PD remains unclear, the link between LRRK2 and the immune system provides an intriguing possibility for a potential pathogenic mechanism as well as aid in the identification of potential markers of LRRK2-related immune function that could inform therapeutic development and/or act as potential pharmacodynamic measures of LRRK2 activity.
This study will take advantage of the larger cohorts of LRRK2 G2385R variant carriers with or without PD established by the Chinese Parkinson Study Group in China.
- Conditions
- Parkinson Disease
- Keywords
- LRRK2 G2385R variant, Parkinson's disease, LRRK2 activity
- Medical subject headings
- Parkinson Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Idiopathic PD | PD patients without the LRRK2 G2385R mutation | |
| LRRK2 G2385R PD | PD patients with the LRRK2 G2385R mutation | |
| LRRK2 G2385R carriers | Subjects without PD who screen positive for the LRRK2 G2385R mutation | |
| Controls | Subjects without PD who screen negative for the LRRK2 G2385R mutation |
What is being measured
The primary outcome is the main question the study is designed to answer.
LRRK2 activity
Differences of blood LRRK2 activity measured by the optimized laboratory protocols among LRRK2 G2385R carriers and non-carriers with or without PD
Measured: baseline
Immune function
Immune-related differences between LRRK2 G2385R carriers and non-carriers with or without PD. Immunological measures include (a) distribution of peripheral blood lymphocyte populations: flow cytometry analysis for surface staining of CD19, CD22, CD79A, PAX5 on B cells, and CD11b, CD14, CD16 on monocytes; (b) cytokine profiles in serum: IL-6, IFN-γ, TGF-β, TNF-α; (c) flow cytometry analysis for proteins involved in several LRRK2-related immune signaling pathways: TLR-4, IFN-γ and TGF-β, NF-κB.
Measured: baseline
Secondary outcomes (1)
Clinical symptoms associated with blood LRRK2 activity
Non-motor and motor symptoms are measured using the following methods: Brief Smell Identification Test (B-SIT) , Hamilton Depression Rating Scale (HAM-D) , RBD Questionnaire-Hong Kong (RBDQ-HK), Mini-Mental State Examination (MMSE), Non-Motor Symptoms Scale for Parkinson's Disease (NMSS), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Purdue Pegboard
Measured: baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2020
- Study start22 May 2018
- Primary completion25 Dec 2020
- Study completion25 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Parkinson DiseaseStudies of the same condition, open and under way.
- More trials run by Xuanwu Hospital, BeijingThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 211 participants (actual)
Sponsor and investigators
- Lead sponsor
- Xuanwu Hospital, Beijing
- Sponsor type
- University, hospital or other
- Collaborators
- Michael J. Fox Foundation for Parkinson's Research
- Responsible party
- Principal investigator, Piu Chan, Xuanwu Hospital, Beijing
- Investigators
- Piu Chan, MD, PhD, Principal investigator, Xuanwu Hospital of Capital Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04349865
- Sponsor's protocol ID
- LRRK2G2385R
- Status last verified
- Feb 2021
- First submitted
- 18 Jan 2020
- Last updated
- 9 Feb 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessment of LRRK2 Activity in G2385R Carriers and Markers Predicting Conversion to and Progression of Parkinson's Disease
- ClinicalTrials.gov ID
- NCT04349865
- Acronym / sponsor ID
- LRRK2G2385R
- Conditions
- Parkinson Disease
- Keywords
- LRRK2 G2385R variant, Parkinson's disease, LRRK2 activity
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 211 participants (actual)
- Lead sponsor
- Xuanwu Hospital, BeijingUniversity, hospital or other
- Collaborators
- Michael J. Fox Foundation for Parkinson's Research
- Study start
- 22 May 2018 (actual)
- Primary completion
- 25 Dec 2020 (actual)
- Study completion
- 25 Dec 2020 (actual)
- First posted
- 16 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goals of this study are
- To compare the functional effects of the LRRK2 G2385R variant among carriers with and without Parkinson's disease (PD) and non-carriers with and without PD
- To investigate the relationship between functional effects of the LRRK2 G2385R variant and PD associated phenotype
- To investigate the biomarkers associated with PD conversion in the LRRK2 G2385R variant carriers
- To compare the immune-related differences between PD patients/unaffected individuals with and without the LRRK2 G2385R mutation, and to investigate the effects of immune dysfunction on the clinical expression of PD
Detailed description
Pharmaceutical companies with LRRK2 kinase inhibitor programs are close to Phase 1 clinical testing. Phase II proof-of-concept clinical trials will need to be conducted in LRRK2 manifesting mutation carriers. This is currently a challenging task given the limited availability of this cohort.
While the LRRK2 G2019S mutation is the most common mutation present in Caucasians and certain ethic groups, the G2385R variant has been identified as a risk factor for sporadic PD in the Asian population (Chinese Han, Japanese and Korean). In fact, in these populations, the occurrence of this mutation is thought to be higher than (up to 4% of PD patients) the occurrence of the G2019S mutation in the Caucasian population. In contrast to G2019S, this variant has not been fully characterized. For example, there has been controversy regarding its kinase activity with some reporting higher and others lower activity. A systematic biochemical characterization of the G2385R is necessary to determine if this cohort may be useful in LRRK2 kinase inhibitor trials.
Although there were significant studies on the clinical characterization of LRRK2 risk variant carriers with or without PD, little is known which factor is more specific in predicting the conversion to PD and which biomarker can be used to measure the disease progression. Identifying these clinical phenotype and biomarkers will be critical for studying pharmaceuticals effective for PD.
Several lines of evidence point to a role of LRRK2 in the immune system. Particularly high LRRK2 expression has been discovered in macrophagic and monocytic cells, but not T-cells, leading to speculation of a functional role for LRRK2 in the innate immune system. LRRK2 is also expressed in toll-like receptor 4 (TLR-4)-activated microglia, brain-resident macrophage cells that have been implicated in the pathology of PD brain, and LRRK2 modulates proinflammatory responses in these cells via several immune signaling pathways. Moreover, enhanced neuroinflammation may contribute to neurodegeneration in PD patients carrying LRRK2 mutations. Further, recent genome-wide association studies highlight LRRK2 in the modification of susceptibility to the chronic autoimmune Crohn's disease and Mycobacterium leprae infection, raising the possibility that LRRK2 may contribute to PD through immunogenic mechanisms. Although neuroinflammation as a primary trigger or secondary process linked to PD remains unclear, the link between LRRK2 and the immune system provides an intriguing possibility for a potential pathogenic mechanism as well as aid in the identification of potential markers of LRRK2-related immune function that could inform therapeutic development and/or act as potential pharmacodynamic measures of LRRK2 activity.
This study will take advantage of the larger cohorts of LRRK2 G2385R variant carriers with or without PD established by the Chinese Parkinson Study Group in China.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Idiopathic PD | – | –PD patients without the LRRK2 G2385R mutation |
| LRRK2 G2385R PD | – | –PD patients with the LRRK2 G2385R mutation |
| LRRK2 G2385R carriers | – | –Subjects without PD who screen positive for the LRRK2 G2385R mutation |
| Controls | – | –Subjects without PD who screen negative for the LRRK2 G2385R mutation |
Who may qualify
- Ages
- 55 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- (1) PD patients are from the Chinese National Consortium of Parkinson Disease (CNCPD) cohort; meanwhile, new patients are enrolled from outpatient and inpatient departments. 2) Unaffected subjects are from a large population-based cohort (the Beijing Longitudinal Study of Aging).
Key inclusion criteria (6 listed)
- PD patients:
- Unaffected subjects:
Key exclusion criteria (1 listed)
- □ Clinically significant neurological disorders.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
LRRK2 activity
Time frame: baseline
Differences of blood LRRK2 activity measured by the optimized laboratory protocols among LRRK2 G2385R carriers and non-carriers with or without PD
Immune function
Time frame: baseline
Immune-related differences between LRRK2 G2385R carriers and non-carriers with or without PD. Immunological measures include (a) distribution of peripheral blood lymphocyte populations: flow cytometry analysis for surface staining of CD19, CD22, CD79A, PAX5 on B cells, and CD11b, CD14, CD16 on monocytes; (b) cytokine profiles in serum: IL-6, IFN-γ, TGF-β, TNF-α; (c) flow cytometry analysis for proteins involved in several LRRK2-related immune signaling pathways: TLR-4, IFN-γ and TGF-β, NF-κB.
1 secondary outcome
Clinical symptoms associated with blood LRRK2 activity
Time frame: baseline
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Feb 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Piu Chan, MD, PhD principal investigator
Xuanwu Hospital of Capital Medical University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Parkinson Disease, run by Xuanwu Hospital, Beijing at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
LRRK2 activity (time frame: baseline). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Feb 2021.