Clinical trial NCT04477785: PPMI Clinical - Establishing a Deeply Phenotyped PD Cohort
Official title: The Parkinson's Progression Markers Initiative (PPMI) Clinical - Establishing a Deeply Phenotyped PD Cohort
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Parkinson Disease
Keywords: Parkinson
Bio-markers
Neurodegenerative disorder
Imaging
Prodromal
Genetics
At Risk
Loss of Smell
Lead sponsor: Michael J. Fox Foundation for Parkinson's Research
Sponsor class: OTHER
Collaborators: name: Institute for Neurodegenerative Disorders
First posted: 2020-07-20
Enrollment: 4500
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: In PPMI Clinical up to 4,500 participants will be enrolled and followed longitudinally from approximately 50-55 international clinical sites across a variety of cohorts, including healthy controls, Parkinson disease, PD manifesting gene carriers, and Prodromal (those at risk for developing PD).

Brief summary: The Parkinson Progression Marker Initiative (PPMI) is a longitudinal, observational, multi-center natural history study to assess progression of clinical features, digital outcomes, and imaging, biologic and genetic markers of Parkinson's disease (PD) progression in study participants with manifest PD, prodromal PD, and healthy controls.

The overall goal of PPMI is to identify markers of disease progression for use in clinical trials of therapies to reduce progression of PD disability.

Detailed description: PPMI is a broad program, expanding the goals of the original PPMI study, that includes this PPMI Clinical protocol, as well as other program initiatives such as the PPMI Remote, PPMI Digital App and PPMI Online protocols. Participants in PPMI may be asked to be enrolled in other PPMI program protocols, but depending on their method of recruitment, participants may be enrolled sequentially in varying order, as appropriate. PPMI participants may also be asked to participate in additional PPMI program initiatives (as they are developed), which may only involve a subset of PPMI participants based on their cohort designation and/or site location.

Eligibility criteria: 7.1 Healthy Controls (HC) Note: Active Healthy controls previously enrolled in PPMI do not require re-assessment of eligibility criteria listed below for enrollment in PPMI Clinical. Active participants do need to be able to provide informed consent for PPMI Clinical participation (includes use of a designated research proxy).

7.1.1 Inclusion Criteria (HC)

1. Male or female age 57 years or older at Screening visit.
2. Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.
3. Confirmation that participant is eligible based on Screening SPECT imaging.
4. Able to provide informed consent.
5. Either is male, or is female and meets additional criteria below, as applicable:

   * Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

7.1.2 Exclusion Criteria (HC)

1. First degree relative with PD (i.e., biologic parent, sibling, child).
2. Current or active clinically significant neurological disorder (in the opinion of the Investigator).
3. Previously obtained MRI scan with evidence of clinically significant neurological disorder (in the opinion of the Investigator).
4. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
5. Current treatment with anticoagulants (e.g., coumadin, heparin, oral thrombin inhibitors) that might preclude safe completion of the lumbar puncture.
6. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
7. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
8. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.

7.2 Parkinson's Disease (PD) Note: Active PD participants previously enrolled in PPMI do not require re-assessment of eligibility criteria listed below for enrollment in PPMI Clinical. Active participants do need to be able to provide informed consent for PPMI Clinical participation (includes use of a designated research proxy).

7.2.1 Inclusion Criteria (PD)

1. Male or female age 30 years or older at Screening Visit.
2. A diagnosis of Parkinson's disease for 2 years or less at Screening Visit.
3. Not expected to require PD medication within at least 6 months from Baseline.
4. Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia); OR either asymmetric resting tremor or asymmetric bradykinesia.
5. Hoehn and Yahr stage I or II at Baseline.
6. Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.
7. Confirmation that participant is eligible based on Screening SPECT imaging.
8. Able to provide informed consent.
9. Either is male, or is female and meets additional criteria below, as applicable:

   * Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

7.2.2 Exclusion Criteria (PD)

1. Currently taking levodopa, dopamine agonists, MAO-B inhibitors, amantadine or another PD medication, except for low-dose treatment of restless leg syndrome (with permission of medical monitor).
2. Has taken levodopa, dopamine agonists, MAO-B inhibitors or amantadine within 60 days of Baseline visit.
3. Has taken levodopa or dopamine agonists prior to Baseline visit for more than a total of 90 days.
4. Atypical PD syndromes due to either drugs (e.g., metoclopramide, flunarizine, neuroleptics) or metabolic disorders (e.g., Wilson's disease), encephalitis, or degenerative diseases (e.g., progressive supranuclear palsy).
5. A clinical diagnosis of dementia as determined by the investigator.
6. Previously obtained MRI scan with evidence of clinically significant neurological disorder (in the opinion of the Investigator).
7. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
8. Current treatment with anticoagulants (e.g., coumadin, heparin, oral thrombin inhibitors) that might preclude safe completion of the lumbar puncture.
9. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
10. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
11. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.

7.3 Parkinson's Disease (PD) with LRRK2 or GBA variant Note: Active PD participants previously enrolled in PPMI do not require re-assessment of eligibility criteria listed below for enrollment in PPMI Clinical. Active participants do need to be able to provide informed consent for PPMI Clinical participation (includes use of a designated research proxy).

7.3.1 Inclusion Criteria (PD ¬- LRRK2 or GBA)

1. Male or female age 30 years or older at Screening Visit.
2. A diagnosis of Parkinson's disease for 2 years or less at Screening Visit.
3. Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia); OR either asymmetric resting tremor or asymmetric bradykinesia.
4. Hoehn and Yahr stage I or II at Baseline.
5. Confirmation of causative LRRK2 or GBA (willingness to undergo genetic testing as part of genetic screening and be informed of genetic testing results, or approved documentation of prior genetic testing results).
6. Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.
7. Confirmation that participant is eligible based on Screening SPECT imaging.
8. Able to provide informed consent.
9. Either is male, or is female and meets additional criteria below, as applicable:

   * Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

7.3.2 Exclusion Criteria (PD - LRRK2 or GBA)

1. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
2. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.
3. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
4. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
5. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.

7.4 Parkinson's Disease (PD) with SNCA or rare genetic variant Note: Active PD participants previously enrolled in PPMI do not require re-assessment of eligibility criteria listed below for enrollment in PPMI clinical. Active participants do need to be able to provide informed consent for PPMI Clinical participation (includes use of a designated research proxy).

7.4.1 Inclusion Criteria (PD - SNCA or rare genetic variant (such as Parkin or Pink1))

1. Male or female age 30 years or older at Screening Visit.
2. Parkinson's disease diagnosis at Screening Visit.
3. Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting tremor or bradykinesia); OR either asymmetric resting tremor or asymmetric bradykinesia.
4. Hoehn and Yahr stage I, II, or III at Baseline.
5. Confirmation of causative SNCA or rare genetic variant (such as Parkin or Pink1) (willingness to undergo genetic testing as part of genetic screening and be informed of genetic testing results, or approved documentation of prior genetic testing results).
6. Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.
7. Confirmation that participant is eligible based on Screening SPECT imaging.
8. Able to provide informed consent.
9. Either is male, or is female and meets additional criteria below, as applicable:

   * Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

7.4.2 Exclusion Criteria (PD - SNCA or rare genetic variant (such as Parkin or Pink1))

1. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
2. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.
3. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
4. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
5. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.

7.5 Prodromal Note: Active Prodromal participants previously enrolled in PPMI do not require re-assessment of eligibility criteria listed below for enrollment in PPMI Clinical. Active participants do need to be able to provide informed consent for PPMI Clinical participation (includes use of a designated research proxy).

The specific predictive eligibility criteria for participants recruited through PPMI Remote to advance to PPMI Clinical will be iteratively optimized based on data collected from these studies.

7.5.1 Inclusion criteria (Prodromal)

For Screening:

1. Confirmation that participant is eligible based on centrally determined predictive criteria including the University of Pennsylvania Smell Identification Test (UPSIT).

   * For participants in PPMI Remote, referral to the clinical site confirms predictive eligibility.
   * For participants identified by the clinical site, predictive criteria are based on generalized risk such as first degree biologic relative, known risk of PD including RBD, or known genetic variants associated with PD risk.

   Additionally, confirmation of UPSIT eligibility during the Screening visit prior to SPECT Imaging.
2. Male or female age 60 years or older (except age 30 years or older for SNCA, or rare genetic variants (such as Parkin or Pink1) participants).
3. Individuals taking any of the following drugs: alpha methyldopa, methylphenidate, amphetamine derivatives or modafinil, must be willing and medically able to hold the medication for at least 5 half-lives before SPECT imaging.
4. Able to provide informed consent.
5. Either is male, or is female and meets additional criteria below, as applicable:

   • Female of childbearing potential who is not pregnant, lactating, or planning pregnancy during the study and has a negative pregnancy test on day of Screening SPECT imaging test prior to injection of DaTscanTM.

   For continuation to Baseline visit and ongoing follow-up:
6. Confirmation that participant is eligible based on \*Screening SPECT imaging.

   * Screening SPECT Imaging eligibility:

Based on the results of the SPECT imaging test, Prodromal participants eligible to continue their participation in PPMI Clinical will be asked to return for their PPMI Clinical baseline visit. Neither the participant nor the site investigator will be made aware of the participant's DAT status during the study.

* It is anticipated that approximately 6,000 participants will complete a screening visit to undergo DAT imaging. Approximately 2,000 participants will be eligible to continue their participation in PPMI Clinical (those not eligible to proceed will remain in PPMI Remote, as applicable).
* All participants with DAT deficit will be eligible to continue their participation in PPMI Clinical. It is estimated that about 75% of eligible participants will have a DAT deficit (defined by a hybrid of visual assessment and quantitative striatal specific binding analysis).
* Some participants without DAT deficit will also be eligible to continue their participation in PPMI Clinical. These participants will be chosen based on DAT binding that is reduced from age expected but it not outside the normal range and/or from individuals with high-risk of PD including RBD, LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1) that do not demonstrate DAT deficit. It is estimated that about 25% of eligible participants will not have a DAT deficit.
* It is anticipated that approximately 30% of the PPMI Clinical prodromal participants with DAT deficit will phenoconvert to motor parkinsonism during a 3 to 5-year follow-up.

7.5.2 Exclusion Criteria (Prodromal)

1. Clinical diagnosis of PD at screening, other parkinsonism, or dementia.
2. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Baseline Visit.
3. Current treatment with anticoagulants (e.g. coumadin, heparin) that might preclude safe completion of the lumbar puncture.
4. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
5. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
6. Currently taking levodopa, dopamine agonists, MAO-B inhibitors, amantadine or another PD medication, except for low-dose treatment of restless leg syndrome (with permission of medical monitor).
7. Has taken levodopa, dopamine agonists, MAO-B inhibitors or amantadine within 60 days of Baseline visit. except for low-dose treatment of restless leg syndrome (with permission of medical monitor).
8. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.

Primary outcomes:
measure: Establish standardized protocols for acquisition, transfer and analysis of clinical, digital, imaging, biologic and genetic data that can be used by the PD research community.
timeFrame: Baseline to 156 months
measure: Comprehensive and uniformly acquired dataset
timeFrame: Baseline to 156 months
measure: Comparison between Rates of Change
timeFrame: Study intervals ranging from 3 months to 156 months
measure: Prevalence of measures of clinical, imaging and biomic outcomes in various subsets
timeFrame: study intervals ranging from baseline to 156 months.
measure: Establish the probability of phenoconversion to PD
timeFrame: study intervals ranging from baseline to 156 months.
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Foundation for Medical Education and Research
state: Arizona
city: Sun City
country: United States
facility: Banner Research Institute
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: Keck School of Medicine of USC
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: New Haven
country: United States
facility: Institute For Neurodegenerative Disorders
state: Connecticut
city: Boca Raton
country: United States
facility: Parkinson's Disease& Movement Disorder Center of Boca Raton
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati/Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health &Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Univ of Washington and VA Puget Sound Health Care System
state: Washington
city: Innsbruck
country: Austria
facility: Innsbruck Medical University
city: Ottawa
country: Canada
facility: The Ottawa Hospital - Civic Campus
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Montréal
country: Canada
facility: McGill University
state: Quebec
city: Hessen
country: Germany
facility: Philipps-University of Marburg
city: Kassel
country: Germany
facility: Paracelsus-Elena Klinik
city: Luebeck
country: Germany
facility: University of Luebeck
city: Tuebingen
country: Germany
facility: University of Tuebingen
city: Athens
country: Greece
facility: Foundation for Biomedical Research of the Academy of Athens
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Salerno
country: Italy
facility: University of Salerno
city: Luxembourg
country: Luxembourg
facility: Parkinson Research Clinic
city: Nijmegen
country: Netherlands
facility: Radboud University
state: Gelderland
city: Lagos
country: Nigeria
facility: Lagos College of Medicine, University of Lagos
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: San Sebastian
country: Spain
facility: Hospital Donostia
city: London
country: United Kingdom
facility: Queen Mary University of London
state: Britain
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle University
state: Tyne And Wear
city: London
country: United Kingdom
facility: Imperial College London
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital Oxford and Oxford University
Study officials:
affiliation: Institute for Neurodegenerative Disorders
name: Kenneth L Marek, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Caroline Tanner, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: