Study to Identify Clinical, Imaging and Biologic Markers of Parkinson Disease Progression
Study to Identify Clinical, Imaging and Biologic Markers of Parkinson Disease Progression
This is a observational, multi-center study to assess progression of clinical features,
 imaging and biologic biomarkers in Parkinson disease (PD) patients compared to healthy
 controls (HC) and in PD patient subtypes.

 The primary objective of this study is to identify clinical, imaging and biologic markers of
 PD progression for use in clinical trials of disease-modifying therapies.
Amendment 14 - 26-Mar-2018 Revised to reflect the implementation of PPMI Wearables and Sensor
 Study Companion Protocol

 Amendment 13 - 20-Nov-2017 Extension of study duration until 2023 for all cohorts (except
 Genetic Registry).

 Amendment 12 - 01-Jun-2017 Planned date of trial extended to September 30, 2020 Ceasing new
 enrollments into the Genetic Registry for LRRK2 and GBA subjects Added Sensor - PPMI
 Companion Study Allow for consent to share contact information with FOUND team at any visit.
 Incorporation of Parkinson's Disease Risk Factor Questionnaire (PD-RFQ) into FOUND.

 Amendment 11 - 01-Apr-2016 Added the collection of peripheral blood mononuclear cells (PBMC)
 from blood samples at interim visits.

 Addition of PPMI Pathology Core/PPMI Brain and Tissue Bank Addition of Gait Assessment
 Companion Study (Select PPMI sites - Genetic Cohort only) Testing for additional GBA
 mutations - previously testing involved testing only for the GBA N370S mutation; however,
 going forward, testing will include tests for additional GBA mutations that are identified as
 being associated with certain ancestry.

 Amendment 10 - 05-Oct-2015 Extended study period for PD and Healthy Control subjects through
 8 years. For Prodromal subjects (RBD and Hyposmic) added iPSC companion study.

 Amendment 9 - 01-Nov-2014 Addition of GBA throughout to document additional testing for GBA
 mutation. Allocation of subjects in Genetic Cohort and Genetic Registry revised to account
 for inclusion of GBA subjects.

 Amendment 8 - 12-May-2014 Companion Protocols: skin biopsy/stem cell; Amyloid Imaging 18F
 Florbetaben; Family History Sub-Study; FOUND in PPMI registry. More detailed description of
 new procedures including: Advance directive for clinical research participation; Extension of
 study period (for SWEDDs with positive scans at Yr. 2) by continuing or re-inviting to study
 and followed (as per PD subjects through Month 60); Objective Parkinson Disease Measurement
 (OPDM) finger tapping measurement.

 Amendment 7 - 14-Oct-2013 Pre-Screening Prodromal - RBD clarifications Pre-Screening Genetic
 Cohort - clarified Assessments/tests clarified, including addition of consent (or withdrawal
 of consent, if applicable) for future contact about future studies and PD family history data
 collection for Genetic cohort subjects as selected visits.

 Amendment 6 - 29-May-2013 Genetics Coordination Core is added to study. The GCC included
 Genetic Cohort PD Subjects, Genetic Cohort Unaffected Subjects and Genetic Registry Subjects.

 Amendment 5 - 27-Nov-2012 Olfactory and RBD subjects added as the Prodromal cohort.

 Amendment 4 - 30-Mar-2012 Addition of 18F-AV-133 VMAT-2 PET Imaging for participating U.S.
 sites and Australia. (Refer to 18F-AV-133-PPMI companion protocol).

 Number of sites increased from 21 to 24. Addition of cognitive categorization and diagnostic
 features assessments.

 Amendment 3 - 15-Jul-2011 Addition of SWEDD subjects to study design. Blood Sampling
 Advisement to collect research samples in a fasted state.

 Amendment 2 - 19-May-2011 Changed visit window from 30 days to 45 days for Baseline visit to
 be completed.

 Section on DAT and SPECT Imaging - section changed to account for subject travel to the
 Institute for Neurodegenerative Disorders to conduct SPECT scanning and injection of either
 DaTSCAN or BCIT.

 Main Protocol - PPMI will be a five-year natural history study (a minimum of 3-year
 involvement for each subject) of de novo idiopathic PD patients and healthy controls. This
 study will also include a SWEDD (subjects without evidence of dopaminergic deficit)and
 Prodromal populations.

 All subjects will be comprehensively assessed at baseline and every three to six months
 thereafter. Subjects will undergo clinical (motor, neuropsychiatric and cognitive) and
 imaging assessments and will donate blood, urine, and cerebral spinal fluid (CSF). A blood
 sample for DNA will be collected. Data will be collected by each site under uniformly
 established protocols and data will be analyzed and stored at designated core facilities.
Inclusion Criteria:

 Parkinson Disease (PD) Subjects:

 -  A diagnosis of Parkinson disease for 2 years or less at Screening.

 -  Confirmation from imaging core that screening DAT scan is consistent with dopamine
 transporter deficit, or if applicable a VMAT-2 PET scan consistent with vesicular
 monoamine transporter deficit.

 -  Not expected to require PD medication with at least 6 months from Baseline.

 -  Male or female age 30 years or older at time of PD diagnosis.

 Healthy Control (HC) Subjects:

 • Male or female age 30 years or older at Screening.

 Exclusion Criteria:

 Parkinson Disease (PD) Subjects:

 -  Currently taking levodopa, dopamine agonists, MAO-B inhibitors, amantadine or other PD
 medication.

 -  Has taken levodopa, dopamine agonists, MAO-B inhibitors or amantadine within 60 days
 of Baseline.

 -  Has taken levodopa or dopamine agonists prior to Baseline for more than a total of 60
 days.

 -  Received any of the following drugs that might interfere with DAT imaging:
 Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or
 amphetamine derivative, within 6 months of Screening.

 -  Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude
 safe completion of the lumbar puncture.

 If applicable, currently taking medications that are known to cause QT-prolongation, or are
 currently taking tetrabenazine (TBZ or amphetamine type medications.

 -  Condition that precludes the safe performance of routine lumbar puncture, such as
 prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant
 coagulopathy or thrombocytopenia.

 -  Use of investigational drugs within 60 days prior to Baseline (dietary supplements
 taken outside of a clinical trial are not exclusionary, e.g., coenzyme Q10).

 Healthy Control (HC) Subjects:

 -  Current or active neurological disorder.

 -  First degree relative with idiopathic PD (parent, sibling, child).

 -  MoCA score < 26.

 -  Received any of the following drugs that might interfere with DAT imaging:
 Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or
 amphetamine derivative, within 6 months of Screening.

 If applicable, currently taking medications that are known to cause QT-prolongation, or are
 currently taking tetrabenazine (TBZ) or amphetamine type medications.

 -  Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude
 safe completion of the lumbar puncture.

 -  Condition that precludes the safe performance of routine lumbar puncture, such as
 prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant
 coagulopathy or thrombocytopenia.

 -  Use of other investigational drugs within 60 days prior to baseline (dietary
 supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme
 Q10).

 SWEDD Subjects:

 All PD criteria apply, as above, except a SWEDD subject must have confirmation from imaging
 core that screening dopamine transporter SPECT scan shows no evidence of dopamine
 transporter deficit or if applicable a VMAT-2 PET scan shows no evidence of vesicular
 monoamine transporter deficit.

 Prodromal Subjects:

 Inclusion Criteria (Prodromal Subjects) 4.2.7.1. Subjects must have at least one of the
 following characteristics:

 Hyposmia:

 1. Male or female age 60 years or older

 2. Confirmation from olfactory core that olfaction as determined by UPSIT is at or below
 the 10th percentile by age and gender

 REM Behavior Disorder (RBD):

 1. Male or female age 60 years or older

 2. Confirmation from sleep core that subject's Polysomnography (PSG) meets criteria for
 RBD

 LRRK2:

 1. Male or female age 60 years or older

 2. Written confirmation or documentation from testing facility that the individual is
 LRRK2 mutation positive 4.2.7.2. Confirmation from imaging core that screening
 dopamine transporter SPECT scan is read as eligible (see below). About 80 subjects
 will have a range of DAT deficit similar to subjects with early PD (mild to moderate
 DAT deficit). About 20 subjects will be selected with no DAT deficit or minimal DAT
 deficit similar in age, gender, and risk profile to those with mild to moderate DAT
 deficit. 4.2.7.3. Ability to provide written informed consent in accordance with Good
 Clinical Practice (GCP), International Conference on Harmonization (ICH), and local
 regulations. 4.2.7.4. Willing and able to comply with scheduled visits, required study
 procedures and laboratory tests. 4.2.7.5. Women may not be pregnant, lactating or
 planning pregnancy during the course of the study. Includes a negative urine pregnancy
 test on day of screening scan prior to injection (DaTSCAN).

 Exclusion Criteria (Prodromal Subjects)

 1. Current or active clinically significant neurological disorder or psychiatric disorder
 (in the opinion of the Investigator).

 2. GDS score greater than or equal to 10 (GDS score of 5 - 9 requires Investigator
 discretion to enter study).

 3. STAI Form Y-1 greater than or equal to 54 requires Investigator discretion to enter
 study.

 4. A clinical diagnosis of dementia63 as determined by the investigator (Appendix 1).

 5. A clinical diagnosis of Parkinson disease at the Screening visit as determined by the
 Investigator.

 6. Received any of the following drugs that might interfere with dopamine transporter
 SPECT imaging: Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate,
 reserpine, or amphetamine derivative, within 6 months of Screening.

 7. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude
 safe completion of the lumbar puncture.

 8. Condition that precludes the safe performance of routine lumbar puncture, such as
 prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant
 coagulopathy or thrombocytopenia.

 9. Any other medical or psychiatric condition or lab abnormality, which in the opinion of
 the investigator might preclude participation.

 10. Use of investigational drugs or devices within 60 days prior to Baseline (dietary
 supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme
 Q10).

 11. Previously obtained MRI scan with evidence of clinically significant neurological
 disorder (in the opinion of the Investigator).

 Genetic Cohort: Parkinson Disease Subjects - Inclusion:

 1. Patients must have at least two of the following: resting tremor, bradykinesia,
 rigidity (must have either resting remor or bradykinesia) or either asymmetric resting
 tremor or asymmetric bradykinesia.

 2. A diagnosis of Parkinson Disease for 7 years or less at screening.

 3. Hoehn and Yahr state <4 at baseline

 4. Male or female age 18 years or older

 5. Willingness to undergo genetic testing and to be informed of genetic testing results.

 6. Confirmation of mutation in LRRK2, GBA or SNCA

 7. For subjects taking any drugs that might interfere with dopamine transporter SPECT
 imaging (Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine or
 amphetamine derivative must be willing and able from a medical standpoint to hold the
 medication for at least 5 half-lives prior to screening DatSCAN(TM) imaging.

 Exclusion:

 1. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude
 safe completion of the lumbar puncture.

 2. Condition that precludes the safe performance of routine lumbar puncture, such as
 prohibitive lumbar spinal disease, bleeding diathesis or clinically significant
 coagulopathy or thrombocytopenia.

 Genetic cohort - Unaffected Individuals

 Inclusion:

 1. Male or female age 45 years or older at baseline with LRRK2 or GBA mutation and/or
 first degree relative with a LRRK2 or GBA mutation or

 2. Male or female age 30 years or older at baseline with a SNCA mutation and/or a first
 degree relative with a SNCA mutation.

 3. Unaffected subjects at high risk of LRRK2, GBA or SNCA mutation due to first degree
 relative with a LRRK2, GBA or SNCA mutation may choose either to be informed of the
 results or remain unaware of the results.

 4. Unaffected subjects from an ethnic or geographic group knkown to have relatively high
 risk of LRRK2, GBA or SNCA mutation such as people of Ashkenazi Jewish or Basques
 descent) and who have a family member (either alive or deceased) who has/had PD must
 be willing to be informed of their own testing results.

 5. Willingness to undergo genetic testing

 6. For subjects taking any of the following drugs that might interfere with dopamine
 transporter SPECT imaging (neuroleptics, metoclopramide, alpha methyldopa,
 methylphenidate, reserpine or amphetamine derivative) must be willing and able from a
 medical standpoint to hold the medication for at least 5 half-lives prior to DatSCAN
 imaging.

 Exclusion:

 1. A clinical diagnosis of PD

 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.

 Genetic Registry - Inclusion:

 1. Individual with a LRRK2, GBA or SNCA mutation and/or a first degree relative with a
 LRRK2, GBA or SNCA mutation.

 2. Male or female age 18 years or older

 3. Willingness to undergo genetic testing, but may choose either to be informed of the
 results or remain unaware of the results.