TITLE: The Parkinson’s Progression Markers Initiative (PPMI) Clinical - Establishing a Deeply Phenotyped PD Cohort
AUTHORS: Kenneth Marek

[DESCRIPTION]
This protocol details the Parkinson’s Progression Markers Initiative (PPMI) Clinical - establishing a deeply phenotyped PD cohort.

[GUIDELINES]
APPENDIX 1 – Healthy Control Schedule Years 0-5  
 
 
                 ABCDEFGHIJKLMNOP1Visit NumberScreeningBaseline (BL)V02V04V05V06R06V08R08V10R10V12bTransition ActivitiesHEvent Driven Modified Visit
2Assessment**Timepoint-60 days06 mths12 (Y1)18 mths24 (Y2)30 mths36 (Y3)42 mths48 (Y4)54 mths60 (Y5)------3Consent Activities4Documentation of Informed ConsentXAs NeededX5Continuing ConsentXXXXX6Research Proxy DesignationXAs Needed (X)
7Consent to share contact informationXAs NeededX8Informed Consent Tracking LogXAs NeededX9General Activities10DemographicsX11Family HistoryX12Socio-EconomicsX13Physical ExaminationX14Program Assessment15Vital Signs (Height and Weight BL + Annually)XX X X X X X X X 16Review Inclusion/Exclusion CriteriaII17Visit StatusX18Screen FailAs NeededAs Needed19Conclusion of Study ParticipationAs Needed20Neurological/Motor Assessments21Participant Motor Function QuestionnairePPPPPP22Freezing and FallsXXXXXX23Neurological ExaminationIIIIIII24MDS-UPDRS Part Ia, Part III Treatment Determination/Motor Exam/Hoehn & YahraIIIIIIIIIII25MDS-UPDRS Part Ib and Part IIPPPPPPPPPPP26Modified Schwab & England ADLIIIIIIIIIII27Features of ParkinsonismIIIIIIIIIII28Other Clinical FeaturesIIIIIIIIIII29Primary Research DiagnosisIIIIIIIIIII30Clinical DiagnosisXXXXXXXXXX X31Non-Motor Assessments32Olfactory Testing (UPSIT)P33REM Sleep Behavior Disorder Screening QuestionnairePPPPPP34Epworth Sleepiness ScalePPPPPP35SCOPA-AUTPPPPPP36Neuro QoLPPPPPP37Cognitive Assessments38Montreal Cognitive Assessment*XXXXXX39Clock Drawing*XXXXXX40Lexical Fluency*XXXXXX41Hopkins Verbal Learning Test-Revised*XXXXXX42Benton Judgment of Line Orientation*XXXXXX43Modified Semantic Fluency (Animals only)*XXXXXX44Letter Number Sequencing*XXXXXX45Symbol Digit Modalities Test*XXXXXX46Trail Making Test (A and B)*XXXXXX47Modified Boston Naming Test*XXXXXX48Cognitive ChangePPPPPPPP49Cognitive CategorizationIIIIII50Neuropsychological Assessments51State-Trait Anxiety Inventory for AdultsPPPPPP52Geriatric Depression ScalePPPPPP53QUIP PPPPPP54Clinical and Biological Samples55Clinical Lab blood sampleX56Research Biosamples (blood + urine)XXXXXXXX57Lumbar punctureXXXXXX58Skin biopsydXXXXc59Imaging Activities60Pregnancy Test (prior to tracer injection), if applicableX61Dopamine ImagingX62MRIX63Safety and General Health64#Adverse EventsXXXXXXX65Adverse Event Telephone Assessment XXXXXXX66Current Medical Conditions ReviewXXXXXXXXXXXX67Concomitant Medication ReviewXXXXXXXXXXXX68Participation in Other Studies As NeededAs Needed69Report of PregnancyAs Needed


APPENDIX 2 – PD / PD Genetic Schedule Years 0 – 5 
 


                 ABCDEFGHIJKLMNOP1Visit NumberScreeningBaseline (BL)V02V04V05V06R06V08R08V10R10V12bTransition ActivitiesHEvent Driven Modified Visit2Assessment**Timepoint-60 days06 mths12 (Y1)18 mths24 (Y2)30 mths36 (Y3)42 mths48 (Y4)54 mths60 (Y5)------3Consent Activities4Documentation of Informed ConsentXAs NeededX5Continuing ConsentXXXXX6Research Proxy DesignationXAs NeededX7Consent to share contact informationXAs NeededX8Informed Consent Tracking LogXAs NeededX9General Activities10DemographicsXX11Family
  HistoryXX12Socio-EconomicsXX13Physical ExaminationX14Program AssessmentXXXXXXXXX15Clinical Global Impression (CGI)IIIIII16Vital Signs (Height and Weight BL + Annually)XXXXXXXXX17Review Inclusion/Exclusion CriteriaII18Visit StatusXXXXXXXXXXXX19Screen FailAs NeededAs Needed20Conclusion of Study ParticipationAs Needed21 Neurological/Motor Assessments22Participant Motor Function Questionnaire PPPPPP23Freezing and FallsXXXXXX24PD Diagnosis HistoryI25Neurological  ExaminationIIIIII26Initiation of Dopaminergic TherapyXXXXXXXXXX27MDS-UPDRS Part Ia, Part III Treatment Determination/Motor Exam/Hoehn & Yahra,dIIIIIIIIIII28MDS-UPDRS Part Ib and Part II PPPPPPPPPPP29Modified Schwab & England ADL IIIIIIIIIII30MDS-UPDRS Part IVdIIIIIIIIII31MDS-UPDRS Repeat Part III/Hoehn & Yahra,dIIIIIII32Features of ParkinsonismIIIIIIIIIII33Other Clinical FeaturesIIIIIIIIIII34Primary Research DiagnosisIIIIIIIIIII35Clinical DiagnosisXXXXXXXXXXX36Non-Motor Assessments37Olfactory Testing (UPSIT)P38REM Sleep Behavior Disorder Screening QuestionnairePPPPPP39Epworth Sleepiness ScalePPPPPP40SCOPA-AUTPPPPPP41Participant Global Impression (PGI)PPPPPP42Neuro QoLPPPPPP43Cognitive Assessments44Montreal Cognitive Assessment*XXXXXX45Clock Drawing*XXXXXX46Lexical Fluency*XXXXXX47Hopkins Verbal Learning Test-Revised*XXXXXX48Benton Judgment of Line Orientation*XXXXXX49Modified Semantic Fluency (Animals only)*XXXXXX50Letter Number Sequencing*XXXXXX51Symbol Digit Modalities Test*XXXXXX52Trail Making Test (A and B)*XXXXXX53Modified Boston Naming Test*XXXXXX54Cognitive ChangePPPPPPPP55Cognitive CategorizationIIIIII56Neuropsychological Assessments57State-Trait Anxiety Inventory for AdultsPPPPPP58Geriatric Depression ScalePPPPPP59QUIP PPPPPP60Clinical and Biological Samples61Clinical Lab blood sampleX62Research Biosamples (blood + urine)XXXXXXXX63Lumbar punctureXXXXXX64Skin biopsyfXXXXc65Imaging Activities66Pregnancy Test (prior to tracer injection), if applicableXXXX67Dopamine ImagingXXXX68MRI XXXX69Safety and General Health70#Adverse EventsXXXXXXX71Adverse Event Telephone AssessmentXXXXXXX72Current Medical Conditions ReviewXXXXXXXXXXXX73Concomitant Medication ReviewXXXXXXXXXXXX74LEDD Concomitant Medication LogAs Needed75Participation in Other StudiesAs Needed76Surgery for PD LogAs Needed77Report of PregnancyAs Needed



APPENDIX 3 – Prodromal Schedule Years 0 – 5 
 


                 ABCDEFGHIJKLMNOP1Visit NumberSC (SPECT)BL (Clinic)R01V04R04V06R06V08R08V10R10V12bTransition ActivitiesHEvent Driven Modified Visit2Assessment**Timepoint-60 days06 mths12 (Y1)18 mths24 (Y2)30 mths36 (Y3)42 mths48 (Y4)54 mths60 (Y5)------ 3Consent Activities4Documentation of Prodromal Screening
  ConsentX  5Documentation of Informed Consent XAs NeededX6Continuing Consent XXXXX  7Research Proxy Designation XAs NeededX8Consent to share contact information XAs NeededX9Informed Consent Tracking LogXXAs Needed 10Pre-Screening Activities11Prodromal History X  12Olfactory Testing (UPSIT) P g  13General Activities14DemographicsXX 15Family HistoryXX 16Socio-EconomicsXX 17Physical Examination X  18Vital Signs (Height and Weight BL +  Annually) XXXXXX  19Review Inclusion/Exclusion CriteriaII  20Program Assessment  XXXXXXXXXXX  21Clinical Global Impression (CGI)  IIIIII  22Visit Status XXXXXXXXXXXX  23Screen FailAs NeededAs Needed24Conclusion of Study Participation    As Needed 25 Neurological/Motor Assessments26Participant Motor Function Questionnaire PPPPPP  27Freezing and Falls  XXXXXX  28Neurological Examination  IIIIII  29Initiation of Dopaminergic Therapy  XXXXXXXXX  30MDS-UPDRS Part Ia, Part III Treatment Determination/Motor Exam/Hoehn & Yahra,dIIIIIIIIII  31MDS-UPDRS Part Ib and Part II  PPPPPPPPPPP  32Modified Schwab & England ADL  IIIIIIIIIII  33MDS-UPDRS Part IVd IIIIIIIIII  34MDS-UPDRS Repeat Part III/Hoehn & Yahra,d IIIII  35Features of Parkinsonism  IIIIIIIIIII  36Other Clinical Features IIIIIIIIIII  37Primary Research Diagnosis  IIIIIIIIIII  38Clinical Diagnosis  XXXXXXXXXXX  39Non-Motor Assessments40Olfactory Testing (UPSIT)  PPPPP  41REM Sleep Behavior Disorder Screening QuestionnairePPPPPP 42Epworth Sleepiness Scale  PPPPPP  43SCOPA-AUT  PPPPPP  44Participant Global Impression (PGI)  PPPPPP  45Neuro QoL  PPPPPP  46Cognitive Assessments47Montreal Cognitive Assessment*  XXXXXX  48Clock Drawing*  XXXXXX  49Lexical Fluency*  XXXXXX  50Hopkins Verbal Learning Test-Revised* XXXXXX  51Benton Judgment of Line Orientation*  XXXXXX  52Modified Semantic Fluency (Animals  only)* XXXXXX  53Letter Number Sequencing*  XXXXXX  54Symbol Digit Modalities Test*  XXXXXX  55Trail Making Test (A and B)*  XXXXXX  56Modified Boston Naming Test*  XXXXXX  57Cognitive Change  PPPPPP  58Cognitive Categorization  IIIIII  59Neuropsychological Assessments60State-Trait Anxiety Inventory for Adults PPPPPP  61Geriatric Depression Scale  PPPPPP  62QUIP  PPPPPP  63Clinical and Biological Samples64Clinical Lab blood sample XXj  65Research Biosamples XMXXXXXX  66Lumbar puncture  XXXXXX  67Skin biopsyfXXjXXXc 68Imaging Activities69Pregnancy Test (prior to tracer injection), if applicableXXXX  70Dopamine Imaging XXXX  71MRI  XXXX  72Safety and General Health73#Adverse EventsXX  74Adverse Event Telephone Assessment XX  75Current Medical Conditions Review As     NeededXXXXXXXXXXX  76Concomitant Medication Review XXXXXXXXXXXX  77Participation in Other Studies  As Needed78LEDD Concomitant Medication Log  As Needed79Surgery for PD Log  As Needed80Report of PregnancyAs Needed


APPENDIX 4 – Healthy Control Schedule Years 6+ 


                      ABCDEFGHIJKLMNOPQRSTU1   Visit NumberR12V13R13V14R14V15R15V16R16V17R17V18R18V19R19AnnualRemotebTransition ActivitiesHEvent Driven Modified Visit2Assessment**Timepoint66 mths72 (Y6)78 mths84 (Y7)90 mths96 (Y8)102 mths108 (Y9)114 mths120 (Y10)126 mths132 (Y11)138 mths144 (Y12)150 mths156+ (Y13+)162 mths+------3Consent Activities4Documentation of Informed ConsentAs NeededX5Continuing Consent XXXXXXXX 6Consent to share contact informationAs Needed7Research Proxy DesignationAs Needed8Informed Consent Tracking LogAs Needed9General Activities10Demographics X 11Family HistoryX 12Socio-EconomicsX 13Program AssessmentXXXXXXXXXXXXXXXXX 14Vital Signs + Height and WeightXXXXXXXX 15Visit StatusXXXXXXXXXXXXXXXXX 16Screen FailAs Needed 17Conclusion of Study ParticipationAs Needed18Neurological/Motor Assessments19Participant Motor Function QuestionnairePPPPPPPP 20Freezing and FallsXXXXXXXX 21Neurological ExaminationIIIIIIII 22MDS-UPDRS Part Ia, Part III Treatment Determination/Motor Exam/Hoehn & YahraIIIIIIIIIIIIIIIII 23MDS-UPDRS Part Ib and Part II P P P P P P P P P P P P P P P P P  24Modified Schwab & England ADLIIIIIIIIIIIIIIIII 25Features of Parkinsonism IIIIIIIIIIIIIIIII 26Other Clinical FeaturesIIIIIIIIIIIIIIIII 27Primary Research DiagnosisIIIIIIIIIIIIIIIII 28Clinical DiagnosisXXXXXXXXXXXXXXXXX 29Non-Motor Assessments30REM Sleep Behavior Disorder Screening QuestionnairePPPPPPPP 31Epworth Sleepiness Scale PPPPPPPP 32SCOPA-AUTPPPPPPPP 33Neuro QoLPPPPPPPP 34Cognitive Assessments                   35Montreal Cognitive Assessment* XXXXXXXX 36Clock Drawing* XXXXXXXX 37Lexical Fluency*XXXXXXXX 38Hopkins Verbal Learning Test-Revised*XXXXXXXX 39Benton Judgment of Line Orientation*XXXXXXXX 40Modified Semantic Fluency (Animals only)*XXXXXXXX 41Letter Number Sequencing*XXXXXXXX 42Symbol Digit Modalities Test* XXXXXXXX 43Trail Making Test (A and B)* XXXXXXXX 44Modified Boston Naming Test* XXXXXXXX 45Cognitive ChangePPPPPPPP 46Cognitive Categorization IIIIIIII 47Neuropsychological Assessments48State-Trait Anxiety Inventory for AdultsPPPPPPPP 49Geriatric Depression ScalePPPPPPPP 50QUIPPPPPPPPP 51Clinical and Biological Samples52Research Biosamples (blood + urine)XXXXXXXX 53Lumbar punctureXXXXXX 54Skin biopsydXc 55Safety and General Health56#Adverse EventsXXXX 57Adverse Event Telephone Assessment XXXX 58Current Medical Conditions ReviewXXXXXXXXXXXXXXXXX 59Concomitant Medication ReviewXXXXXXXXXXXXXXXXX 60Participation in Other StudiesAs Needed61Report of Pregnancy As Needed


APPENDIX 5 – PD / PD Genetic Schedule Years 6+
 


                      ABCDEFGHIJKLMNOPQRSTU1Visit NumberR12V13R13V14R14V15R15V16R16V17R17V18R18V19R19AnnualRemotebTransition ActivitiesHEvent Driven Modified Visit2Assessment**Timepoint66 mths72 (Y6)78 mths84 (Y7)90 mths96 (Y8)102 mths108 (Y9)114 mth120 (Y10)126 mths132 (Y11)138 mths144 (Y12)150 mths156+ (Y13+)162 mths+------3Consent Activities4Documentation of Informed ConsentAs NeededX5Continuing Consent XXXXXXXX6Consent to share contact informationAs Needed7Research Proxy DesignationAs Needed8Informed Consent Tracking LogAs Needed9General Activities10DemographicsX11Family HistoryX12Socio-EconomicsX13Program AssessmentXXXXXXXXXXXXXXXXX14Clinical Global Impression (CGI)IIIIIIII15Vital Signs + Height and Weight XXXXXXXX16Visit Status XXXXXXXXXXXXXXXXX17Screen FailAs Needed18Conclusion of Study ParticipationAs Needed19Neurological/Motor Assessments20Participant Motor Function QuestionnairePPPPPPPP21Freezing and FallsXXXXXXXX22Neurological ExaminationIIIIIIII23Initiation of Dopaminergic Therapy XXXXXXXXXXXXXXXXX24MDS-UPDRS Part Ia, Part III Treatment Determination/Motor Exam/Hoehn & Yahra,dIIIIIIIIIIIIIIII25MDS-UPDRS Part Ib and Part II  PPPPPPPPPPPPPPPP26Modified Schwab & England ADLIIIIIIIIIIIIIIIII27MDS-UPDRS Part IVdIIIIIIIIIIIIIIIII28MDS-UPDRS
  Repeat Part III/Hoehn & Yahra, dIIIIIIII29Features of Parkinsonism IIIIIIIIIIIIIIIII30Other Clinical FeaturesIIIIIIIIIIIIIIIII31Primary Research DiagnosisIIIIIIIIIIIIIIIII32Clinical Diagnosis XXXXXXXXXXXXXXXXX33Non-Motor Assessments34REM Sleep Behavior Disorder Screening QuestionnairePPPPPPP35Epworth Sleepiness Scale PPPPPPPP36SCOPA-AUT PPPPPPPP37Participant Global Impression (PGI) PPPPPPPP38Neuro QoLPPPPPPPP39Cognitive Assessments                   40Montreal Cognitive Assessment*XXXXXXXX41Clock Drawing*XXXXXXXX42Lexical Fluency*XXXXXXXX43Hopkins Verbal Learning Test-Revised*XXXXXXXX44Benton Judgment of Line Orientation*XXXXXXXX45Modified Semantic Fluency (Animals only)*XXXXXXXX46Letter Number Sequencing*XXXXXXXX47Symbol Digit Modalities Test*XXXXXXXX48Trail Making Test (A and B)*XXXXXXXX49Modified Boston Naming Test*XXXXXXXX50Cognitive ChangePPPPPPPP51Cognitive CategorizationIIIIIIII52Neuropsychological Assessments53State-Trait Anxiety Inventory for AdultsPPPPPPPP54Geriatric Depression ScalePPPPPPPP55QUIPPPPPPPPP56Clinical and Biological Samples57Research Biosamples (blood + urine)XXXXXXXX58Lumbar punctureXXXX59Skin biopsyfX c60Safety and General Health61#Adverse EventsXXXX62Adverse Event Telephone Assessment XXXX63Current Medical Conditions Review XXXXXXXXXXXXXXXXX64Concomitant Medication Review XXXXXXXXXXXXXXXXX65Participation in Other Studies As Needed66LEDD Concomitant Medication Log As Needed67Surgery for PD Log As Needed68Report of PregnancyAs Needed


APPENDIX 6 - Prodromal Schedule Years 6 + 


                      ABCDEFGHIJKLMNOPQRSTU1Visit NumberR12V13R13V14R14V15R15V16R16V17R17V18R18V19R19AnnualRemotebTransition ActivitiesHEvent Driven Modified Visit2Assessment**Timepoint66 mths72 (Y6)78 mths84 (Y7)90 mths96 (Y8)102 mths108 (Y9)114 mth120 (Y10)126 mths132 (Y11)138 mths144 (Y12)150 mths156+ (Y13+)162 mths+------3Consent Activities4Documentation of Informed ConsentAs NeededX5Continuing Consent XXXXXXXX6Consent to share contact informationAs Needed7Research Proxy DesignationAs Needed8Informed Consent Tracking Log 9General Activities10DemographicsX11Family HistoryX12Socio-EconomicsX13Program AssessmentXXXXXXXXXXXXXXXXX14Clinical Global Impression (CGI)IIIIIIII15Vital Signs + Height and Weight XXXXXXXX16Visit Status XXXXXXXXXXXXXXXXX17Screen FailAs Needed18Conclusion of Study ParticipationAs Needed19Neurological/Motor Assessments20Participant Motor Function QuestionnairePPPPPPPP21Freezing and FallsXXXXXXXX22Neurological ExaminationIIIIIIII23Initiation of Dopaminergic Therapy XXXXXXXXXXXXXXXXX24MDS-UPDRS Part Ia, Part III Treatment Determination/Motor Exam/Hoehn & Yahra,dIIIIIIIIIIIIIIII25MDS-UPDRS Part Ib and Part II PPPPPPPPPPPPPPPPP26Modified Schwab & England ADLIIIIIIIIIIIIIIIII27MDS-UPDRS Part IVdIIIIIIIIIIIIIIIII28MDS-UPDRS Repeat Part III/Hoehn & Yahra, dIIIIIIII29Features of Parkinsonism IIIIIIIIIIIIIIIII30Other Clinical FeaturesIIIIIIIIIIIIIIIII31Primary Research DiagnosisIIIIIIIIIIIIIIIII32Clinical Diagnosis XXXXXXXXXXXXXXXXX33Non-Motor Assessments34REM Sleep Behavior Disorder Screening QuestionnairePPPPPPP35Epworth Sleepiness Scale PPPPPPPP36SCOPA-AUT PPPPPPPP37Participant Global Impression (PGI) PPPPPPPP38Neuro QoLPPPPPPPP39Cognitive Assessments                   40Montreal Cognitive Assessment*XXXXXXXX41Clock Drawing*XXXXXXXX42Lexical Fluency*XXXXXXXX43Hopkins Verbal Learning Test-Revised*XXXXXXXX44Benton Judgment of Line Orientation*XXXXXXXX45Modified Semantic Fluency (Animals only)*XXXXXXXX46Letter Number Sequencing*XXXXXXXX47Symbol Digit Modalities Test*XXXXXXXX48Trail Making Test (A and B)*XXXXXXXX49Modified Boston Naming Test*XXXXXXXX50Cognitive ChangePPPPPPPP51Cognitive CategorizationIIIIIIII52Neuropsychological Assessments53State-Trait Anxiety Inventory for AdultsPPPPPPPP54Geriatric Depression ScalePPPPPPPP55QUIPPPPPPPPP56Clinical and Biological Samples57Research Biosamples (blood + urine)XXXXXXXX58Lumbar punctureXXXX59Skin biopsyfX c60Safety and General Health61#Adverse EventsXXXX62Adverse Event Telephone Assessment XXXX63Current Medical Conditions Review XXXXXXXXXXXXXXXXX64Concomitant Medication Review XXXXXXXXXXXXXXXXX65Participation in Other Studies As Needed66LEDD Concomitant Medication Log As Needed67Surgery for PD Log As Needed68Report of PregnancyAs Needed


[STEPS]
SECTION: PURPOSE OF STUDY
3. Primary Objectives of PPMI Clinical:
The primary objectives include to:


SECTION: PURPOSE OF STUDY
3.1. 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. This protocol will build on the existing PPMI infrastructure.
SECTION: PURPOSE OF STUDY
3.5. Evaluate the probability of phenoconversion to PD for individuals with prodromal PD enrolled in the prodromal cohorts (including individuals with RBD, olfactory loss, a LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and/ or other risk factors for PD with and without DAT deficit).
SECTION: PURPOSE OF STUDY
3.4. Confirm existing and identify novel clinical, digital, imaging, biologic and genetic PD progression markers to identify quantitative individual measures or combinations of measures that demonstrate optimum interval change in study participants with PD diagnosis (including patients with a LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1)) and individuals with prodromal Parkinson’s disease (including individuals with RBD, olfactory loss, a LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and/or other risk factors for PD with and without DAT deficit in comparison to healthy controls or in sub-sets of study participants with PD diagnosis or prodromal PD defined by baseline assessments, progression milestones and/or rate of clinical, digital, imaging, biologic and genetic change, or other measures.
SECTION: PURPOSE OF STUDY
3.3. Use clinical and biological data to estimate the mean rates of change and the variability around the mean of clinical, digital, imaging, biological and genetic outcomes in study participants with PD diagnosis (including patients with a LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and individuals with prodromal Parkinson’s disease (including individuals with REM sleep behavior disorder (RBD)), olfactory loss, LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and/or other risk factors for PD with and without dopamine transporter (DAT) deficit and in healthy participants.
SECTION: PURPOSE OF STUDY
3.2. Develop a comprehensive and uniformly acquired clinical, digital and imaging dataset and repository of biological and genetic samples that would be available to the PD research community to test hypotheses of the underlying molecular pathobiology of PD, enable modeling of PD progression to identify clinical and/or data driven PD progression sub-sets, and inform studies testing PD therapeutics (for examples, clinical trials targeting synuclein, LRRK2, GBA as well as other targets).
SECTION: PURPOSE OF STUDY
1. The Parkinson Progression Marker Initiative (PPMI) is a longitudinal, observational, multicenter 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.
SECTION: PURPOSE OF STUDY
2. 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.
SECTION: PURPOSE OF STUDY
4. Secondary Objectives
The secondary objectives include the following:
SECTION: PURPOSE OF STUDY
4.1. Conduct preliminary clinical, digital, imaging, biologic and genetic markers verification studies on promising biological markers in study subsets and/or using stored collected samples.
SECTION: PURPOSE OF STUDY
4.2. Compare biomarker signatures for study participants with PD diagnosis without known genetic variant to those with known genetic variant (including LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1)).
SECTION: PURPOSE OF STUDY
4.3. Compare biomarker signatures in study participants with PD diagnosis to individuals with prodromal PD enrolled in the prodromal cohorts (including individuals with RBD, olfactory loss, LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and/or other risk factors for PD with and without DAT deficit).
SECTION: PURPOSE OF STUDY
4.4. Compare biomarker signature between prodromal PD subsets including individuals with RBD, olfactory loss, LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and/or other risk factors for PD with and without DAT deficit.
SECTION: PURPOSE OF STUDY
4.5. Develop and test risk paradigms to establish the sequence of early prodromal events (clinical, imaging, biologic changes) in individuals with prodromal PD enrolled in the prodromal cohorts (including individuals with RBD, olfactory loss, LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and/or other risk factors for PD with and without DAT deficit) including testing early signal of risk in the associated PPMI Online and PPMI Remote studies.
SECTION: STUDY OUTCOMES
5. Key PPMI outcomes will be longitudinal change in clinical (motor and non-motor) scales (e.g., MDS-UPDRS, MoCA), Patient Reported Outcomes (PROs) and digital outcomes, quantitative imaging (DAT, SBR, and MRI midbrain melanin), and biologic measures of synuclein, lysosomal function, and analytes related to neurodegeneration (e.g., neurofilament light chain inflammation).
SECTION: STUDY OUTCOMES
6. Detailed demographic, clinical and biological data will be collected to test specific hypotheses in subsequent analyses and other associated protocols. In addition, data quality metrics including compliance with study procedures, quality metrics related to biosamples and completeness of data collection will be monitored on an ongoing basis.
SECTION: BACKGROUND AND RATIONALE
7. Background for PPMI Clinical
SECTION: BACKGROUND AND RATIONALE
7.1. The defining motor features of Parkinson’s disease (PD) are characterized by their insidious onset and inexorable but heterogenous progression. Reliable and well-validated biomarkers to monitor PD progression would dramatically accelerate research into both PD etiology and therapeutics. Much progress has been made in identifying and assessing PD biomarkers, and yet no fully validated biomarker or set of biomarkers for PD are currently available.
SECTION: BACKGROUND AND RATIONALE
7.2. Nonetheless, there is increasing evidence that assessment of clinical, digital, imaging outcomes and measurement of analytes from blood, cerebral spinal fluid (CSF), urine, and tissue has already begun to provide crucial tools for PD drug development and for understanding the pathobiology of PD (1-3).
SECTION: BACKGROUND AND RATIONALE
7.3. During the past decade, the PPMI study has established a longitudinal clinical and biomarker data resource on approximately 1,500 participants including cohorts with idiopathic PD, PD with genetic variants, prodromal participants and healthy controls. PPMI is an observational, international, multi-center study designed to establish biomarker defined cohorts and to identify PD progression biomarkers to improve understanding of disease etiology and course and to provide critical tools to enhance the likelihood of success of PD therapeutic trials (ClinicalTrials.gov NCT01141023). PPMI is a collaborative effort of PD researchers with expertise in biomarker development, PD clinical study design and implementation, bioinformatics, statistics, and data management. The study is a publicprivate partnership of academic researchers, the Michael J Fox Foundation (MJFF) and pharmaceutical, biotech, government and foundation partners.
SECTION: BACKGROUND AND RATIONALE
7.4. The overall goal of PPMI is to examine clinical, imaging, genetic and biospecimen PD progression markers that individually or in combination will rapidly demonstrate interval change in PD patients in comparison to Healthy Controls (HC) or in sub-sets of PD patients defined by baseline assessments, genetic variants, progression milestones and/or rate of clinical, imaging or biospecimen change. PPMI has established standardized protocols for acquisition, transfer and analysis of clinical, imaging, genetic and biospecimen data that can be used by the PD research community. Importantly PPMI is committed to data and biospecimen sharing. PPMI data are available to the research community on the PPMI website as it is collected and there have been more than ten million downloads of PPMI data (as of May 2022). PPMI biospecimens are available by application to the PPMI Biospecimen Review Committee with more than three hundred requests, as of May 2022. All PPMI standardized protocols and PPMI data are available at http://www.ppmi-info.org (4, 5).
SECTION: BACKGROUND AND RATIONALE
7.5. PPMI is the most comprehensive natural history dataset of PD participants and serves, according to its original purpose, as a key resource for drug development and understanding of the clinical and biological features of PD progression. The study has demonstrated the enormous value of comprehensive, longitudinal within subject biomarker assessment. PPMI has developed a robust study infrastructure with well-developed study leadership and governance, committed enrolling sites, and expert study cores (data, imaging, biorepositories, bioinformatics, genetics) to ensure the ongoing collection and analysis of study data. The study has developed and expanded methods to enroll biomarker defined cohorts requiring dopamine imaging deficit for inclusion in the PD cohort, piloted methods to establish prodromal cohorts of hyposmic and RBD participants and has established a novel centralized strategy to enroll participants with PD genetic mutations (6-8). PPMI has also demonstrated the feasibility and safety of multicenter longitudinal collection of CSF (9).
SECTION: BACKGROUND AND RATIONALE
7.6. PPMI longitudinal data has and continues to be acquired and reported to inform clinical trials for PD. PPMI data has detailed the progression of the MDS-UPDRS (both off and on PD meds) and cognitive and behavioral outcomes enabling sample size estimation to detect changes in progression due to therapeutic intervention (10-12), Predictors of key PPMI outcomes and of need for PD therapy have also been evaluated (13, 14). Progression of dopamine transporter (DAT) imaging has demonstrated a robust reduction in PD participants and PPMI DAT eligibility data has contributed to its qualification by the EMA as an enrichment biomarker (11, 15, 16). Longitudinal analysis of synuclein, amyloid and tau from CSF has demonstrated a persistent reduction in synuclein and tau in PD participants compared to healthy controls but without significant progression (17-19). Several other analytes/pathways have also been assessed including neurofilament light chain, catecholamines, and the lysosomal pathway providing additional data (PPMI website) showing modest changes with progression with reports in press.
SECTION: BACKGROUND AND RATIONALE
7.7. A key strength of PPMI is the within participant design so that multiple biomarkers are assessed in each participant. This strategy has enabled studies identifying PD subsets based several biomarkers and has allowed various multi-modal biomarkers to be compared. There have been several efforts to develop biomarker derived subsets of PD to define risk and/or disease progression to further understand the heterogeneity of PD. Combining genetics with clinical and imaging biomarkers has resulted in a genetic risk score that may be helpful in predicting PD and has led to additional studies combining whole genome sequencing, RNA transcriptomics and clinical and imaging markers (20). DAT and MRI imaging have been combined with clinical outcomes to explore PD subsets and PD pathobiology (21-23). Combining clinical motor outcomes with behavioral and cognitive outcomes has provided insight to the timing of non-motor PD disability and utility of current non-motor scales to track early disease (24-27). Examining biomarkers in genetic cohorts has further identified specific imaging and biologic markers that may distinguish those cohorts (28, 29). PPMI offers the opportunity to examine multiple biomarker data streams and analysis strategies for these data including unbiased data analysis approaches have identified possible PD subsets and predictors of progression (30).
SECTION: BACKGROUND AND RATIONALE
7.8. PPMI has also developed prodromal cohorts defined by olfaction, RBD or genetic variant to pilot longitudinal assessment of biomarker prodromal PD and establish biomarkers that predict the development of motor parkinsonism. Overwhelming scientific data have demonstrated that the molecular pathology of Parkinson’s disease begins long in advance of clinical symptoms. Longitudinal densely phenotyped follow-up of individuals at high risk to develop PD would enable both understanding of the progression of disease during the prodromal period and could ultimately lead to the testing of therapies that might prevent the onset of manifest motor PD. The Movement Disorder Society proposed criteria to define prodromal PD for research (31, 32). Prior studies including the Parkinson Associated Risk Syndrome (PARS) study and long-term RBD studies have further demonstrated that prodromal PD participants with hyposmia or RBD with abnormal imaging have high risk of the onset of motor PD within 3-5 years (33, 34). Pilot prodromal data from the ongoing PPMI study has shown that about 35% of hyposmic and RBD participants with abnormal DAT converted to motor PD within four years. Data from the unaffected LRRK2 and GBA mutation carriers shows less than 10 % of participants with abnormal DAT, but mild increase in motor and non-motor features compared to healthy subjects (35).
SECTION: BACKGROUND AND RATIONALE
7.9. PPMI has been committed to open-source data with rapid sharing of all PPMI data to the PD community (36) . This data resource now includes clinical (motor and non-motor), digital, imaging, and genetic data plus a robust biorepository including blood, CSF, urine and induced pluripotent stem (IPS) cells.
SECTION: BACKGROUND AND RATIONALE
8. Rationale for PPMI Clinical
SECTION: BACKGROUND AND RATIONALE
8.1. While the PPMI study has made substantial progress as outlined above, the program offers the opportunity to expand and transform the use of biomarkers to test hypotheses of the underlying molecular pathobiology of PD, enable modeling of PD progression to identify clinical and/or biologic data driven PD progression sub-sets and inform studies testing PD therapeutics including clinical trials targeting synuclein, LRRK2, GBA and other targets.
SECTION: BACKGROUND AND RATIONALE
8.2. There is a consensus that a new PPMI cohort is necessary to further develop and validate biomarkers for PD progression and prodromal PD to enable therapeutic development. Further advances in molecular genetics, neurobiology, imaging technology, wearable sensor and remote assessment technology and radiochemistry have provided new tools that may be useful in identification of such biomarkers for further studies of therapies that may slow or prevent PD disability.
SECTION: BACKGROUND AND RATIONALE
8.3. The goal of this new initiative is to extend the current PPMI consortium of academic centers, PD foundations, pharmaceutical and biotech companies. government agencies, and active study participants, to establish and validate markers of PD progression across the spectrum of disease from prodromal PD to more advanced disease.
SECTION: BACKGROUND AND RATIONALE
8.4. In PPMI Clinical, established tools will also be further validated and new technologies including neuroimaging modalities, digital biomarkers, biochemical markers in the CSF and plasma, genetic markers, and early clinical disease markers will be investigated. We will continue to standardize biomarker acquisition and assessment and to establish well-defined quantitative biomarker outcomes that are consistent among many research sites and laboratories.
SECTION: BACKGROUND AND RATIONALE
8.5. Core laboratories for biomarker analysis will be used for uniformity of analyses and quality control. A major focus of this biomarker consortium will be to extend PPMI infrastructure to new biomarkers and new cohorts, particularly those with prodromal PD. Longitudinal data will include Participant Reported Outcomes with an emphasis on outcomes that reflect participant function throughout the course of PD.
SECTION: BACKGROUND AND RATIONALE
8.6. This approach to biomarker development is ambitious and requires collaboration among many in academics, industry, government, and the public sector. However, PPMI has demonstrated that such an approach is feasible. PPMI has been successful in providing opensource data and fostering effective collaboration.
SECTION: BACKGROUND AND RATIONALE
8.7. The unmet need for therapeutics that slow or prevent the disability of PD coupled with the enormous value of biomarkers to enable and accelerate clinical studies highlights the need for this strategy to identify and validate biomarkers of PD progression throughout the course of disease.
SECTION: STUDY DESIGN
9. PPMI Clinical is a longitudinal, observational, multi-center natural history study to assess progression of clinical features, digital outcomes, and imaging, biologic and genetic markers of PD progression in study participants with PD diagnosis (including patients with LRRK2, GBA, SNCA or rare genetic variants and individuals with prodromal Parkinson’s disease (including individuals with RBD, olfactory deficit, LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1) and/or other risk factors for PD with and without DAT deficit and healthy controls.
SECTION: STUDY DESIGN
10. All participants will be comprehensively assessed for a minimum of 5 years. Participants will undergo clinical (motor, neuropsychiatric and cognitive) and imaging assessments, and will donate biosamples including blood, urine, and cerebral spinal fluid (CSF) and skin biopsy. Participants will also be asked to respond to targeted questionnaires and provide digital data as part of the PPMI Online and PPMI Digital App protocols (under separate consent).
SECTION: STUDY COHORTS
11. 
 
Current PPMI participants: All participants across all cohorts enrolled in PPMI will be eligible to continue participation in PPMI. Participants may belong to one of the following PPMI cohorts (healthy control, PD, PD with LRRK2 variant, PD with GBA variant, PD with SNCA mutation or rare genetic variants, prodromal with LRRK2 variant, prodromal with GBA variant, prodromal with SNCA or rare genetic variants, prodromal with hyposmia, prodromal with RBD). These participants will be invited to join the cohort in PPMI that matches their original designation (n=up to 1150).
SECTION: STUDY COHORTS
12. Healthy controls (n=up to 120).
SECTION: STUDY COHORTS
13. Parkinson’s disease (PD) participants who are recently diagnosed and untreated (n= up to 700).
SECTION: STUDY COHORTS
14. PD manifesting gene carriers with a LRRK2 or GBA variant (n=up to 250), SNCA or other rare genetic variant (such as Parkin or Pink1) (n= up to 60).
SECTION: STUDY COHORTS
15. Prodromal PD (at risk for PD) (n=up to 2220)
SECTION: STUDY COHORTS
15.1. Hyposmia (generalized risk) (n= up to 1260)
SECTION: STUDY COHORTS
15.2. RBD (n= up to 500)
SECTION: STUDY COHORTS
15.3. LRRK2 variant (n= up to 200)
SECTION: STUDY COHORTS
15.4. GBA variant (n= up to 200)
SECTION: STUDY COHORTS
15.5. SNCA or other rare genetic variants (n= up to 60)
SECTION: RECRUITMENT METHODS
16. 
 
Prodromal Participants – Path to PPMI Clinical
SECTION: RECRUITMENT METHODS
16.1. Potential prodromal participants may be eligible to participate in PPMI Clinical based on participation in the PPMI Online protocol (information from online questionnaires assessing general health and risk of PD), PPMI Remote (information from additional remote testing including olfactory testing), or directly from a clinical site based on known PD risk, such as possible REM sleep behavior disorder (RBD) or known genetic variants associated with increased PD risk.
SECTION: RECRUITMENT METHODS
17. Identifying Participants with Genetic Variants
Identifying participants with genetic variants will require targeted recruitment.
SECTION: RECRUITMENT METHODS
16.2. Eligible individuals from PPMI Remote will be referred to PPMI clinical sites to consent to participation in PPMI Clinical and undergo their prodromal SPECT imaging screening visit.
SECTION: RECRUITMENT METHODS
16.4. All prodromal participants will be screened for hyposmia via a smell identification test such as the University of Pennsylvania Smell Identification Test (UPSIT), either in PPMI Remote or, if recruited by the clinical site, as part of the PPMI Clinical Prodromal Screening visit, which may also include blood and skin samples.
SECTION: RECRUITMENT METHODS
16.3. Individuals identified by a clinical site with known risks may also be considered to consent to participation in PPMI Clinical and undergo a Prodromal Screening visit.
SECTION: RECRUITMENT METHODS
17.1. Prodromal participants with a genetic variant will be identified in large part through a centralized recruitment process, as well as from clinical sites.

Centralized Recruitment – Indiana University: Individuals who do not have Parkinson Disease will be centrally screened by Indiana University. Potential participants maybe identified by targeted campaigns. These potential participants will undergo remote screening and will undergo genetic testing (saliva kits) and/or telegenetic counseling (under separate consent). These participants will be eligible to participate in other PPMI program protocols, such as PPMI Online, PPMI Remote, PPMI Digital App, and subsequently, if eligible would be referred to a study site and further assessed for eligibility to enroll in PPMI Clinical.

Clinical Site Recruitment of Unaffected Persons with Genetic Variants: Individuals who do not have Parkinson Disease may also be recruited from the clinical sites. In general, these sites will have prior access to participants and families with genetic variants due to site interest and/or specific geographic location. Individuals being considered for participation in PPMI Clinical at clinical sites who may have these genetic variants, but have not previously undergone genetic testing, will undergo evaluation including genetic testing and genetic counseling (under separate consent from the PPMI Clinical study). Existing documentation of lab results will be provided to the PPMI Screening Core for further review and confirmation of eligibility for inclusion in PPMI Clinical. The outcome of this review will be provided to the clinical site, and if approved, these participants would not require additional genetic testing. Individuals with identified LRRK2, GBA, SNCA, or rare genetic variants that meet genetic criteria would be further assessed by the referring site team for eligibility to enroll in PPMI Clinical.
SECTION: RECRUITMENT METHODS
17.2. Parkinson’s Disease participants with a genetic variant will be identified in large part through a centralized recruitment process, as well as from clinical sites.

Centralized Recruitment – Indiana University: Individuals with PD with an increased risk for carrying LRRK2 and/or GBA variants will be centrally screened by Indiana University. Potential participants maybe identified by targeted campaigns. These potential participants will undergo remote genetic testing (saliva kits) and/or telegenetic counseling (under separate consent). If found to carry a pathogenic PD variant, these participants will be referred to a study site and further assessed for eligibility to enroll in PPMI Clinical. If found to not carry a pathogenic PD variant, these participants will be referred to PPMI Online if not already enrolled.

Clinical Site Recruitment: Individuals with PD and LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1 variants), may also be recruited from the clinical sites. In general, these sites will have prior access to participants and families with genetic variants due to site experience and/or specific geographic location. Individuals being considered for participation in PPMI Clinical at clinical sites who may have these genetic variants, but have not previously undergone genetic testing, will undergo evaluation including genetic testing and genetic counseling (under separate consent from the PPMI Clinical study). Documentation of lab results will be provided to the PPMI Screening Core for further review and confirmation of eligibility for inclusion in PPMI Clinical. The outcome of this review will be provided to the clinical site, and if approved, these participants would not require additional genetic testing. Individuals with identified LRRK2, GBA, SNCA, or rare genetic variants that meet genetic criteria would be further assessed by the referring site team for eligibility to enroll in PPMI Clinical.
SECTION: PARTICIPANT ELIGIBLITY
18. Healthy Controls (HC)-Inclusion Criteria
 

SECTION: PARTICIPANT ELIGIBLITY
18.1. Male or female age 30 years or older at Screening visit.
SECTION: PARTICIPANT ELIGIBLITY
18.2. 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.
SECTION: PARTICIPANT ELIGIBLITY
18.3. Confirmation that participant is eligible based on Screening SPECT imaging.
SECTION: PARTICIPANT ELIGIBLITY
18.4. Able to provide informed consent.
SECTION: PARTICIPANT ELIGIBLITY
18.5. 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.
SECTION: PARTICIPANT ELIGIBLITY
19. Healthy Controls (HC)-Exclusion Criteria
SECTION: PARTICIPANT ELIGIBLITY
19.1. First degree relative with PD (i.e., biologic parent, sibling, child).
SECTION: PARTICIPANT ELIGIBLITY
19.2. Current or active clinically significant neurological disorder (in the opinion of the Investigator).
SECTION: PARTICIPANT ELIGIBLITY
19.3. Previously obtained MRI scan with evidence of clinically significant neurological disorder (in the opinion of the Investigator).
SECTION: PARTICIPANT ELIGIBLITY
19.4. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
SECTION: PARTICIPANT ELIGIBLITY
19.5. Current treatment with anticoagulants (e.g., coumadin, heparin, oral thrombin inhibitors) that might preclude safe completion of the lumbar puncture.
SECTION: PARTICIPANT ELIGIBLITY
19.6. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
SECTION: PARTICIPANT ELIGIBLITY
19.7. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
SECTION: PARTICIPANT ELIGIBLITY
19.8. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.
SECTION: PARTICIPANT ELIGIBLITY
20. Parkinson’s Disease (PD)-Inclusion Criteria 
 

SECTION: PARTICIPANT ELIGIBLITY
20.1. Male or female age 30 years or older at Screening Visit.
SECTION: PARTICIPANT ELIGIBLITY
20.2. A diagnosis of Parkinson’s disease for 2 years or less at Screening Visit.
SECTION: PARTICIPANT ELIGIBLITY
20.3. Not expected to require PD medication within at least 6 months from Baseline.
SECTION: PARTICIPANT ELIGIBLITY
20.4. 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.
SECTION: PARTICIPANT ELIGIBLITY
20.5. Hoehn and Yahr stage I or II at Baseline.
SECTION: PARTICIPANT ELIGIBLITY
20.6. 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.
SECTION: PARTICIPANT ELIGIBLITY
20.7. Confirmation that participant is eligible based on Screening SPECT imaging.
SECTION: PARTICIPANT ELIGIBLITY
20.8. Able to provide informed consent.
SECTION: PARTICIPANT ELIGIBLITY
20.9. 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.
SECTION: PARTICIPANT ELIGIBLITY
21. Parkinson’s Disease (PD)-Exclusion Criteria
SECTION: PARTICIPANT ELIGIBLITY
21.1. 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).
SECTION: PARTICIPANT ELIGIBLITY
21.2. 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).
SECTION: PARTICIPANT ELIGIBLITY
21.3. Has taken levodopa or dopamine agonists prior to Baseline visit for more than a total of 90 days.
SECTION: PARTICIPANT ELIGIBLITY
21.4. 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).
SECTION: PARTICIPANT ELIGIBLITY
21.5. A clinical diagnosis of dementia as determined by the investigator.
SECTION: PARTICIPANT ELIGIBLITY
21.6. Previously obtained MRI scan with evidence of clinically significant neurological disorder (in the opinion of the Investigator).
SECTION: PARTICIPANT ELIGIBLITY
21.7. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
SECTION: PARTICIPANT ELIGIBLITY
21.8. Current treatment with anticoagulants (e.g., coumadin, heparin, oral thrombin inhibitors) that might preclude safe completion of the lumbar puncture.
SECTION: PARTICIPANT ELIGIBLITY
21.9. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
SECTION: PARTICIPANT ELIGIBLITY
21.10. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
SECTION: PARTICIPANT ELIGIBLITY
21.11. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.
SECTION: PARTICIPANT ELIGIBLITY
22. Parkinson’s Disease (PD) with LRRK2 or GBA variant-Inclusion Criteria
 

SECTION: PARTICIPANT ELIGIBLITY
22.1. Male or female age 30 years or older at Screening Visit.
SECTION: PARTICIPANT ELIGIBLITY
22.2. A diagnosis of Parkinson’s disease for 2 years or less at Screening Visit.
SECTION: PARTICIPANT ELIGIBLITY
22.3. 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.
SECTION: PARTICIPANT ELIGIBLITY
22.4. Hoehn and Yahr stage I or II at Baseline.
SECTION: PARTICIPANT ELIGIBLITY
22.5. 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).
SECTION: PARTICIPANT ELIGIBLITY
22.6. 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.
SECTION: PARTICIPANT ELIGIBLITY
22.7. Confirmation that participant is eligible based on Screening SPECT imaging.
SECTION: PARTICIPANT ELIGIBLITY
22.8. Able to provide informed consent.
SECTION: PARTICIPANT ELIGIBLITY
22.9. 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.
SECTION: PARTICIPANT ELIGIBLITY
23. Parkinson’s Disease (PD) with LRRK2 or GBA variant-Exclusion Criteria
SECTION: PARTICIPANT ELIGIBLITY
23.1. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
SECTION: PARTICIPANT ELIGIBLITY
23.2. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.
SECTION: PARTICIPANT ELIGIBLITY
23.3. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
SECTION: PARTICIPANT ELIGIBLITY
23.4. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
SECTION: PARTICIPANT ELIGIBLITY
23.5. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.
SECTION: PARTICIPANT ELIGIBLITY
24. Parkinson’s Disease (PD) with SNCA or rare genetic variant (such as Parkin or Pink1))-Inclusion Criteria
 

SECTION: PARTICIPANT ELIGIBLITY
24.1. Male or female age 30 years or older at Screening Visit.
SECTION: PARTICIPANT ELIGIBLITY
24.2. Parkinson’s disease diagnosis at Screening Visit.
SECTION: PARTICIPANT ELIGIBLITY
24.3. 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.
SECTION: PARTICIPANT ELIGIBLITY
24.4. Hoehn and Yahr stage I, II, or III at Baseline.
SECTION: PARTICIPANT ELIGIBLITY
24.5. 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).
SECTION: PARTICIPANT ELIGIBLITY
24.6. 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.
SECTION: PARTICIPANT ELIGIBLITY
24.7. Confirmation that participant is eligible based on Screening SPECT imaging.
SECTION: PARTICIPANT ELIGIBLITY
24.8. Able to provide informed consent.
SECTION: PARTICIPANT ELIGIBLITY
24.9. 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.
SECTION: PARTICIPANT ELIGIBLITY
25. Parkinson’s Disease (PD) with SNCA or rare genetic variant (such as Parkin or Pink1))-Exclusion Criteria
SECTION: PARTICIPANT ELIGIBLITY
25.1. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Screening visit.
SECTION: PARTICIPANT ELIGIBLITY
25.2. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.
SECTION: PARTICIPANT ELIGIBLITY
25.3. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
SECTION: PARTICIPANT ELIGIBLITY
25.4. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
SECTION: PARTICIPANT ELIGIBLITY
25.5. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.
SECTION: PARTICIPANT ELIGIBLITY
26. Prodromal
 
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.

SECTION: PARTICIPANT ELIGIBLITY
27. Inclusion criteria (Prodromal)
For Screening:
SECTION: PARTICIPANT ELIGIBLITY
27.1. 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.
            1. Additionally, confirmation of UPSIT eligibility during the Screening visit prior to SPECT Imaging.
SECTION: PARTICIPANT ELIGIBLITY
27.2. 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).
SECTION: PARTICIPANT ELIGIBLITY
27.3. 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.
SECTION: PARTICIPANT ELIGIBLITY
27.4. Able to provide informed consent.
SECTION: PARTICIPANT ELIGIBLITY
27.5. 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.
SECTION: PARTICIPANT ELIGIBLITY
27.6. For continuation to Baseline visit and ongoing follow-up:
Confirmation that participant is eligible based on *Screening SPECT imaging.
 

SECTION: PARTICIPANT ELIGIBLITY
28. Exclusion Criteria (Prodromal)
SECTION: PARTICIPANT ELIGIBLITY
28.1. Clinical diagnosis of PD at screening, other parkinsonism, or dementia.
SECTION: PARTICIPANT ELIGIBLITY
28.2. Received any of the following drugs: dopamine receptor blockers (neuroleptics), metoclopramide and reserpine within 6 months of Baseline Visit.
SECTION: PARTICIPANT ELIGIBLITY
28.3. Current treatment with anticoagulants (e.g. coumadin, heparin) that might preclude safe completion of the lumbar puncture.
SECTION: PARTICIPANT ELIGIBLITY
28.4. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
SECTION: PARTICIPANT ELIGIBLITY
28.5. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
SECTION: PARTICIPANT ELIGIBLITY
28.6. 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).
SECTION: PARTICIPANT ELIGIBLITY
28.7. 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).
SECTION: PARTICIPANT ELIGIBLITY
28.8. Any other reason that, in the opinion of the investigator, would render the participant unsuitable for study enrollment.
SECTION: OBTAINING INFORMED CONSENT
29. Consent Process
SECTION: OBTAINING INFORMED CONSENT
29.1. The procedures and requirements of the study, together with any potential hazards/risks, and the freedom to withdraw from participation in the study at any time, will be explained to each potential participant as part of the consent process.
SECTION: OBTAINING INFORMED CONSENT
29.2. The consent process will take place in a space that allows for privacy and confidentiality and should allow for enough time for the individual to consider participation and ask any questions. Consent will be obtained by the study Investigator or delegated study staff, as applicable.
SECTION: OBTAINING INFORMED CONSENT
29.3. Sites may obtain informed consent remotely (e.g., by telephone or videoconference) after the consent form has been provided to the potential participant (e.g., mail, email, e-sign document), as deemed appropriate by the Investigator.
SECTION: OBTAINING INFORMED CONSENT
29.4. If the individual agrees to participation, the signed consent will be returned to the site (e.g., mail, email, e-sign document) for signature by the person obtaining consent before any research procedures begin.
SECTION: OBTAINING INFORMED CONSENT
29.5. Each participant will sign such an informed consent to document agreement to participate in the study, as well as to document HIPAA authorization and compliance with GDPR regulation, as applicable. The signed informed consent may be uploaded to a secure portal for remote monitoring.
SECTION: OBTAINING INFORMED CONSENT
29.6. It is the responsibility of the Investigator (or as delegated to the person obtaining consent) to make sure that the participant understands what she/he is agreeing to and that informed consent is obtained before the participant is involved in any protocol-defined procedures, including screening procedures.
SECTION: OBTAINING INFORMED CONSENT
29.7. Each participant will be provided a copy of the consent form(s). There will be two consents for the PPMI Clinical prodromal cohort as they will initially consent to the Screening visit and then, if eligible, will consent to the longitudinal PPMI Clinical procedures. In addition to obtaining initial consent to participate, Investigators must ensure ongoing consent as part of this longitudinal study (for example, documentation at an annual study visit that the participant continues to understand the procedures and requirements of the study).
SECTION: OBTAINING INFORMED CONSENT
30. Identification of Research Proxy
SECTION: OBTAINING INFORMED CONSENT
30.1. There is the potential for development of cognitive impairment in participants over the course of study participation. Therefore, in accordance with good clinical practices in ensuring each participant’s ability to give ongoing informed consent, identification of a research proxy will enable continued participation for participants whose ability to consent becomes compromised.
SECTION: OBTAINING INFORMED CONSENT
30.2. Identification of a research proxy through use of the Advance Directive for Clinical Research Participation form, enables participants to clarify their preferences, thus guiding the substitute decision maker and the Investigator. It is noted that the accepted term and/or required directive for a designated substitute decision maker (also known as a Legally Authorized Representative/LAR) may vary on a country/state/provincial basis.
SECTION: OBTAINING INFORMED CONSENT
30.3. During the initial consent process, or at any time during assessment of ongoing consent as applicable, a participant may identify a substitute decision maker who will be permitted to carry out the participant’s wishes regarding continued participation (or not) in PPMI Clinical should the participant lose the ability to make his or her own decision. The site Investigator will exercise clinical judgment and ascertain a participant’s ability to continue giving informed consent. This ascertainment may include a discussion including review of the study purpose, differences between research and clinical assessments, and the risks of study participation.
SECTION: OBTAINING INFORMED CONSENT
30.4. If deemed necessary by the Investigator, the participant will be approached about contacting the person(s) named in the advance directive while the participant is still capable of discussing the need to invoke the research proxy. Should the Investigator deem it necessary to invoke the LAR, the designated individual will be contacted by telephone, if not already present at the study visit, to discuss the next steps for determining the participant’s continuing participation.
SECTION: OBTAINING INFORMED CONSENT
30.5. Designation of a LAR is voluntary; thus, identification of a substitute decision maker is not required to participate in PPMI. However, if in the absence of a substitute decision maker the Investigator deems a participant no longer able to provide ongoing consent, the participant will be withdrawn from the study.
SECTION: OBTAINING INFORMED CONSENT
30.6. Documentation is required for completion of the Advance Directive, routine review of the participant’s continuing ability to give informed consent at each visit, any discussion with the participant’s substitute decision maker, as well as documentation of informed consent (and assent of the participant) should a LAR be invoked.
SECTION: OBTAINING INFORMED CONSENT
31. Permission to be Contacted for Follow Up of Persons with Neurologic Disease
SECTION: OBTAINING INFORMED CONSENT
31.1. The Follow Up of Persons with Neurologic Disease (FOUND) study (Caroline Tanner MD, Principal Investigator, University of California-San Francisco (UCSF)) provides a parallel, centralized system to prospectively collect vital status and disease progression information from persons with parkinsonism, related disorders and healthy controls who are participating in clinical research studies.
SECTION: OBTAINING INFORMED CONSENT
31.2. Participation in FOUND complements in-person assessment, enables continuity of follow up of individuals who complete or withdraw from a study, and may also aid in PPMI study retention. Participation in FOUND will enable centralized contact both during and after completion of PPMI, using convenient methods for systematic data collection (e.g., regular mail, telephone, internet contacts).
SECTION: OBTAINING INFORMED CONSENT
31.3. During the initial consent process for PPMI Clinical, and as needed at subsequent follow up visit, participants will be asked if their contact information may be shared with the FOUND study team at UCSF. The participant’s decision will be documented in the PPMI informed consent and the PPMI database. If a participant agrees, UCSF will be notified and will proceed with contacting the individual to invite participation into FOUND. UCSF will share with the referring sites their participants’ status in FOUND at regular intervals.
SECTION: OBTAINING INFORMED CONSENT
31.4. PPMI participants who have incomplete enrollment in FOUND will be asked by the site to discuss this with the participant to identify if there are any issues impeding enrollment and address any such issues. The data collected from the FOUND study will be uploaded into the PPMI data repository at the Laboratory of Neuro Imaging (LONI), The Institute for Neuroimaging and Informatics in Los Angeles, California, at regular intervals. 
SECTION: OBTAINING INFORMED CONSENT
32. Permission to be Contacted from Pathology Core
SECTION: OBTAINING INFORMED CONSENT
32.1. Post-mortem analysis of brain tissue is pivotal to Parkinson’s disease research, allowing researchers to examine changes noted in the post-mortem brain tissue and correlate it with changes in neuropsychological, imaging, and biomic data collected throughout the PPMI Clinical study. However, there is limited availability to this type of tissue, leading to organized efforts to facilitate brain donation planning through the PPMI Pathology Core.
SECTION: OBTAINING INFORMED CONSENT
32.2. The PPMI Pathology Core is a collaboration between Indiana University and Stanford University. Indiana University is responsible for coordinating all logistics up-to death, including obtaining consent, identifying a removal specialist, coordinating with clinical sites, and interfacing with the decedent’s family. Indiana University also ensures the removal specialist follows outlined removal and shipping guidelines to transfer the whole brain to the Stanford team, while a small tissue sample is shipped to Indiana University for DNA extraction. Stanford University is responsible for post-mortem activities including receiving specimens, specimen dissection and preparation for embedding and processing, performing neuropathological evaluation of tissue, coordinating clinicopathological case conferences (CPCs), and long-term storage of brain tissue samples.
SECTION: OBTAINING INFORMED CONSENT
32.3. For clinical sites based in the United States, site coordinators will discuss the PPMI Pathology Core with participants and provide them with an information at initial consent to PPMI, or subsequent study visits as applicable. Participants will be asked to provide permission to allow their contact information to be transferred to the Pathology Core team. Participants may also contact the team at Indiana University directly to learn more about enrollment.
SECTION: OBTAINING INFORMED CONSENT
32.4. The Pathology Core team will contact participants to discuss tissue donation further and answer questions. If participants are agreeable to continue with donation planning, they will first be asked to sign a consent form that reflects their intent to donate brain tissue and other relevant tissue upon death. This consent is approved by the Indiana University IRB. After consent, the participant will provide additional information to help with their local planning and coordination.
SECTION: OBTAINING INFORMED CONSENT
32.5. The Indiana and Stanford University teams will also provide support to international PPMI sites that are interested in contributing to PPMI brain tissue donation activities. Stanford University will work with neuropathologists at local sites to ensure the harmonization of brain tissue collection and processing across all PPMI sites. Indiana University will help establish workflows from consent to donation and ensure regulatory considerations are met for participant inclusion in the PPMI Pathology Core.
SECTION: OBTAINING INFORMED CONSENT
32.6. The data collected across the Pathology Core will be collated by the team at Indiana University and transferred to the PPMI data repository at the Laboratory for Neuro Imaging (LONI), The Institute for Neuroimaging and Informatics in Los Angeles, California, at regular intervals. It is possible that collected tissues may be distributed to approved researchers for future analysis.
SECTION: PARTICIPANT INFORMATION AND STUDY ID
33. Participant Profile Information:

When a participant provides consent to participate, the following participant identifiers may be collected in the electronic database capture (EDC) system: full name (first name, middle name, last name), home address, phone number, email address, date of birth, sex, city/municipality of birth and country of birth.
 
 

 
SECTION: PARTICIPANT INFORMATION AND STUDY ID
34. Participant ID Number:

A Participant ID number will be assigned to all PPMI Clinical participants, if not previously assigned under another PPMI program protocol. Active PPMI participants transitioning into this PPMI protocol will keep their previously assigned PPMI ID number, while newly enrolled participants will be assigned a new 6-digit ID number, generated automatically by EDC. The PPMI Participant ID number will be used to identify a participant on all study related documentation (e.g., clinical database, biological specimens).
SECTION: STUDY VISIT PROCEDURES
35. Screening, Baseline and Annual study visits may occur over the period of more than one day due to the complexity of the visits and resources required at the site. The date each assessment was completed will be captured within the EDC system and will therefore reflect whether a visit required a duration of more than one day to complete.
SECTION: STUDY VISIT PROCEDURES
36. The Baseline visit should be completed within 60 days of the Screening visit. Follow up 6 month and annual visits should be completed with +45 days of the target visit date. Out of window visits will not be considered a protocol deviation but will be monitored throughout the study for each site.
SECTION: STUDY VISIT PROCEDURES
37. Assessments that require completion by the Site Investigator (or trained designee) include the following (it is the goal of the study that the clinical assessments be conducted by the same individual throughout the study):

Informed Consent
Research proxy designation
Review Inclusion/Exclusion criteria
Neurological Examination
MDS-UPDRS Parts Ia, III, IV, MDS-UPDRS Repeat Part III, Hoehn & Yahr
Modified Schwab & England ADL
Features of Parkinsonism
Other Clinical Features
Primary Research Diagnosis
Cognitive Categorization
Clinical Global Impression (CGI)
SECTION: STUDY VISIT PROCEDURES
38. Out of Clinic Annual Visits:

To enable continued involvement of participants in the PPMI Clinical study and enhance study retention, participants who are unable to attend annual visits in person due to reasons such as participant burden, advanced disease, and/or participant safety (e.g., such as COVID- 19), are eligible for assessment out of the clinic. Options for Out of Clinic visits include virtual visits by video link (i.e., telemedicine), enhanced telephone, phone/audio only, or inhome assessments in which PPMI site staff travel to the participant’s home. Sites should complete as many assessments indicated for the scheduled annual visit as is feasible, based on the type of out of clinic visit conducted and ability to do an assessment (i.e., videoconference versus in-home or audio only). Sites will record visit status, indicating if the visit was OOC, in the EDC.
SECTION: STUDY VISIT PROCEDURES
39. Active PPMI Transitioning Participants
 

Active participants previously enrolled in PPMI will not require a Screening or Baseline visit. Participants who agree to continue participation and transition into PPMI Clinical will enroll into PPMI and complete the next planned study visit based on the last completed visit in PPMI (or based on timing of site activation and participant’s visit schedule). The process of obtaining informed consent, including an explanation of study activities, is described in the cohort visits below and will be conducted prior to completing any PPMI Clinical study activities. Participants transitioned into PPMI Clinical will be followed for a minimum of 5 years, either in person or remotely according to the respective cohort’s schedule of activities. Active PPMI participants choosing not to continue into PPMI Clinical protocol will be tagged by the site as “Complete”.
SECTION: STUDY VISIT PROCEDURES
40. Healthy Control, PD and PD Genetic Cohort Visits
SECTION: STUDY VISIT PROCEDURES
40.1. HC, PD and PD Genetic Screening Visit

 


All newly enrolled participants in these cohorts will undergo a screening evaluation prior to the Baseline visit. The Screening visit will take about 8 hours to complete (could occur over more than one day).

During the informed consent process the following activities will also be described, as applicable:

Discuss start of or ongoing participation in other relevant PPMI Program protocols (e.g., such as PPMI Online, PPMI Digital)
An explanation of FOUND in PPMI will be given and participants will be asked permission to have their contact information sent to the FOUND coordinating site at UCSF so that UCSF study team can contact them about their interest in participation. Participants may take time to review and complete at a subsequent visit.
An explanation of the PPMI Pathology Core will be given and participants will be asked permission to have their contact information sent to the Pathology Core study team. Alternatively, participants may take time to review and complete this information at a subsequent visit.
An explanation of the purpose and procedures for identification of a substitute decision maker (or research proxy) will be given. Participants may take time to review and complete at a subsequent visit.
SECTION: STUDY VISIT PROCEDURES
40.2. HC, PD and PD Genetic Baseline Visit
 
Once all study procedures are completed, the Investigator (or designee) must ensure that the participant meets eligibility for the relevant cohort in order to continue with longitudinal follow up visits. This Baseline visit is anticipated to take 8 hours (could occur over more than one day).
SECTION: STUDY VISIT PROCEDURES
40.3. HC, PD and PD Genetic Follow up Visits
 
After the Baseline visit is completed, participants will be evaluated in clinic every 6 months for the first two years. Annual visits are anticipated to take about 6-8 hours (could occur over more than one day), while the 6-month in clinic visits will take about 2-4 hours. After two years, all participants will continue to be evaluated every 6 months remotely and annually in the clinic, for a minimum of 5 years of longitudinal follow up visits. Options for Remote 6-month visits include virtual visits by video link or telemedicine, or phone/audio only. The remote 6-month visits will take about 1-2 hours. Sites should complete as many assessments at the Remote (“R”) visit as is feasible, based on how the visit is conducted (i.e., videoconference versus in-home or audio only) and ability to do an assessment.
SECTION: STUDY VISIT PROCEDURES
41. Prodromal Cohort Visits
SECTION: STUDY VISIT PROCEDURES
41.1. Prodromal Screening Visit
 
Participants eligible for PPMI Clinical Prodromal cohort will undergo a screening evaluation, which may include clinical labs, research blood sample, skin biopsy and completion of an UPSIT if recruited directly by the site, as well as SPECT imaging for all participants prior to the Baseline visit. Informed consent for the Prodromal Screening visit will be obtained by the site and eligibility to complete the SPECT imaging confirmed. Sites must have confirmation that a participant is eligible based on the SPECT imaging prior to proceeding to the Baseline visit, at which time the participant will be fully consented to the PPMI Clinical protocol. The Screening Visit will take about 6-8 hours to complete (could occur over more than one day).
SECTION: STUDY VISIT PROCEDURES
41.2. Prodromal Baseline Visit
 
Prodromal cohort participants eligible to proceed to the Baseline visit will first consent to the full PPMI Clinical study. During the informed consent process the following activities will also be described, as applicable:

Discuss start of or ongoing participation in other relevant PPMI Program protocols (e.g., such as PPMI Online, PPMI Digital)
An explanation of FOUND in PPMI will be given and participants will be asked permission to have their contact information sent to the FOUND coordinating site at UCSF so that UCSF study team can contact them about their interest in participation. Participants may take time to review and complete at a subsequent visit.
An explanation of the PPMI Pathology Core will be given and participants will be asked permission to have their contact information sent to the Pathology Core study team. Alternatively, participants may take time to review and complete this information at a subsequent visit.
An explanation of the purpose and procedures for identification of a substitute decision maker (or research proxy) will be given. Participants may take time to review and complete at a subsequent visit.

Once all Baseline study procedures are completed, the Investigator (or designee) must ensure that the participant meets eligibility in order to continue with longitudinal follow up visits. This Baseline visit is anticipated to take about 6-8 hours (could occur over more than one day).
SECTION: STUDY VISIT PROCEDURES
41.3. Prodromal Follow Up Visits
 
After the Baseline visit is completed, participants will be evaluated in clinic annually and remotely every 6 months, for a minimum of 5 years of longitudinal follow up visits. Annual visits are anticipated to take about 6-8 hours (could occur over more than one day). Options for Remote 6-month visits include virtual visits by video link or telemedicine, or phone/audio only. The remote 6-month visits will take about 1-2 hours. Sites should complete as many assessments at the Remote (“R”) visit as is feasible, based on how the visit is conducted (i.e., videoconference versus in-home or audio only) and ability to do an assessment.
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
42. New Clinical Diagnosis

If, after enrollment (i.e., Baseline visit), a PD or Prodromal participant receives a new clinical diagnosis of PD or other neurodegenerative disorder (meaning the clinical diagnosis occurred outside the context of the PPMI research assessments), attempt to schedule an in person PPMI visit as soon as possible after the site is made aware of the new clinical diagnosis.

A participant may be seen up to 3 months in advance of the next scheduled target visit date. If the next scheduled visit is a ‘R’ visit, then the ‘R’ visit should be modified to an in person visit.

SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
42.1. Participant assessed at an annual visit – follow schedule of activities for the respective annual visit.
If Year 3, annual visit SPECT imaging and MRI should be conducted.
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
42.2. Participant is assessed in person at an ‘R’ visit.

In addition to the activities already conducted at an ‘R’ visit, the following other assessments should be administered, including:
Note: Imaging, skin biopsy and lumbar puncture not required
Research biosamples (blood and urine) collection
Vital signs
All Neurological/Motor Assessments, including a full UPDRS
All Non-Motor Assessments, including UPSIT at Year 1, 2 and Year 4 for Prodromal cohort only
All Cognitive Assessments
All Neuropsychological Assessments
Safety and General Health assessments, as applicable

Following completion of an in person visit as described above, resume participant’s regular visit schedule.
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
43. Need for PD Therapy
 
If the site becomes aware that a PD or Prodromal participant is planning to or has already started PD medication, attempt to schedule an in person PPMI visit as soon as possible after the site is made aware. It is preferable to have the participant seen prior to starting medication. If a participant is not assessed in person prior to starting PD medication, conduct the next study visit per the regular visit schedule (participant should hold medication prior to conducting the visit).

A participant may be seen up to 3 months in advance of the next scheduled target visit date of either an annual visit or remote ‘R’ visit.
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
43.1. Participant assessed at an annual visit – follow schedule of activities for the annual visit; no additional activities are required.
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
43.2. Participant is assessed in person at an ‘R’ visit – In addition to the activities already conducted at ‘R’ visit, the following other assessments should be administered, including:

Note: Imaging, skin biopsy and lumbar puncture not required
Research biosamples (blood and urine) collection
Vital signs
All Neurological/Motor Assessments, including a full UPDRS
All Non-Motor Assessments (Note: UPSIT not required)
All Cognitive Assessments
All Neuropsychological Assessments
Safety and General Health assessments, as applicable
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
44. Withdrawal from the Study

If a participant withdraws from the study and does not want to be seen for any more assessments, complete the Conclusion of Participation assessment under the last completed visit.
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
44.1. Withdrawal During Scheduled Visit

If a participant withdraws from the study during a scheduled annual visit, proceed with the visit as outlined in the schedule of activities and complete the Conclusion of Participation assessment.
SECTION: EVENT DRIVEN MODIFICATION OF SCHEDULED VISITS
44.2. Withdrawal Outside Scheduled Visit

If a participant withdraws from the study outside of a scheduled visit, determine whether the participant agrees to be seen for one more in-person visit, or prefers to conduct a remote ‘R’ visit. Complete the Conclusion of Participation assessment once the visit is completed.

1. Withdrawal at remote ‘R’ visit:
Conduct study procedures for that visit schedule of activities
2. Withdrawal at in person annual visit – conduct study procedures for that annual visit schedule of activities, with the following exceptions, as feasible:
Research biosamples(blood and urine) collection – only if not done in the last 3 months
Lumbar puncture for collection of CSF – only if not done in the last 3 months
Skin biopsy – only if not done in the last 6 months, up to Year 4
MRI (Prodromal and PD cohorts only)– only if not done in the last 6 months, up to Year 4
SPECT Imaging (Prodromal and PD cohorts only) – only if not done in the last 6 months, up to Year 4

SECTION: CLINICAL ASSESSMENTS
45. Refer to the PPMI Assessments and eCRF Completion Manual for a detailed description of the clinical assessments and instructions for administration.
SECTION: SAFETY ASSESSMENTS
46. Medical Conditions Review, Physical and Neurological Examination

Medical and family history, as well as a complete physical and neurological exam will be captured on all participants according to the schedule of activities. A neurological exam will also be conducted annually, as well as at the last completed visit if possible.
SECTION: SAFETY ASSESSMENTS
47. Vital Signs/Weight/Height

Pulse rate (supine and standing), blood pressure (supine and standing), and temperature will be determined at every in person visit. The supine blood pressure and pulse rate will be determined after 1-3 minutes of quiet rest and the standing pressure and rate will be determined after 1-3 minutes in the standing position. Weight and height will also be collected at baseline and annually.
SECTION: SAFETY ASSESSMENTS
48. Clinical Laboratory Tests
SECTION: SAFETY ASSESSMENTS
48.1. Routine clinical safety laboratory tests indicated in the table below will be performed at the first visit only for new enrollments (i.e., Screening for PD and Healthy Controls, Screening or Baseline for Prodromal participants). A central laboratory will be implemented in order to conduct identical analysis methods and utilize consistent normal ranges and thus common interpretation of laboratory changes. If not stated otherwise, venous whole blood will be collected in blood collection tubes (vacutainers).
SECTION: SAFETY ASSESSMENTS
48.2. All samples for laboratory analysis must be collected, prepared, labelled, and shipped according to the laboratory’s requirement as detailed in the lab manual. The total amount of blood needed for the clinical safety lab tests will be no more than 5 ml. No more than 60 ml will be drawn at either the Screening or Baseline visit, including both safety and research blood samples.
SECTION: SAFETY ASSESSMENTS
48.3. The coagulation panel (PT/PTT) will be collected and shipped by all sites to the central lab for analysis for the first visit only for new enrollments (i.e., Screening for PD and Healthy Controls, Screening or Baseline for Prodromal participants). Sites have the option, per clinical practice, to collect an additional blood sample to evaluate coagulation results prior to the conduct of post Baseline Visit lumbar puncture assessments. The sample should be sent to a local lab facility for analysis.
SECTION: SAFETY ASSESSMENTS
48.4. Results will be evaluated to determine, in the opinion of the Investigator, whether there are any issues that may preclude conduct of the follow up lumbar puncture. Results should be maintained as part of the participant’s study documents; however, will not be included in the study database.
 
        CENTRAL
  LAB TESTS    METABOLIC PANEL  COMPLETE BLOOD COUNT    Sodium (Na)  White Blood Cell Count (WBC)    Potassium (K)  Red Blood Cell Count (RBC)    Chloride (Cl)  Hemoglobin (Hb)    Carbon Dioxide (CO2)  Hematocrit (HCT)    Blood Urea Nitrogen (BUN)  Platelet Count (PLT)    Glucose      Calcium (Ca)      Creatinine (Crn)      Bilirubin Total      Albumin      Total Protein      Aspartate aminotransferase (AST)      Alanine aminotransferase (ALT)      Alkaline Phosphatase (ALKP)      Uric Acid      Prothrombin time (PT) – Screening Only      Partial
  Thromboplastin Time (PTT) – Screening Only  

SECTION: BIOLOGIC RESEARCH SAMPLING
49. 
 
Blood Samples
SECTION: BIOLOGIC RESEARCH SAMPLING
49.1. Whole blood (about 10 ml), serum (about 30 ml) and plasma (about 10 ml) will be collected to conduct proteomic, metabolomic, genetic and other research analyses. No more than 60 ml will be drawn at any visit, including both clinical safety labs and research blood samples.
SECTION: BIOLOGIC RESEARCH SAMPLING
49.2. It is strongly advised that the research blood samples are collected in a fasted state (i.e., minimum of 8 hours since last meal/food intake) to ensure the quality of samples for future analyses. If fasting is not possible, then participants should be advised to eat a low lipid diet. All research samples will be sent to a central biorepository to be stored indefinitely for research purposes. Samples will be made available to researchers to conduct analyses related to PD and other disorders. Participants will not receive any individual results of research analysis or testing conducted on the biologic samples.
SECTION: BIOLOGIC RESEARCH SAMPLING
50. Urine
SECTION: BIOLOGIC RESEARCH SAMPLING
50.1. Urine (about 10-15 ml) will be collected to conduct analyte analyses.
SECTION: BIOLOGIC RESEARCH SAMPLING
51. Lumbar Puncture / Cerebral Spinal Fluid (CSF)
SECTION: BIOLOGIC RESEARCH SAMPLING
51.1. The lumbar puncture (LP) is performed by the site investigator, or another qualified clinician appointed by the investigator. A lumbar puncture for the collection of 15-20 ml of CSF will be conducted for all participants per the visit schedule unless there is evidence of clinically significant coagulopathy or thrombocytopenia that would interfere with the safe conduct of the procedure. In addition, a LP may be conducted under fluoroscopy as deemed necessary by the site investigator or as per site’s standard practice. The first 2 ml of CSF will be processed for cell count, protein, and glucose levels.
SECTION: BIOLOGIC RESEARCH SAMPLING
51.2. Participants will be closely monitored the day of the procedure for adverse events. Participants will also be contacted by phone 2 to 3 [business/working] days following an LP to assess for any adverse events. The CSF samples will be sent to a central biorepository to be stored indefinitely for research purposes. The CSF samples will be made available to researchers to conduct analyses related to PD and other disorders.
SECTION: BIOLOGIC RESEARCH SAMPLING
52. Skin Biopsy
SECTION: BIOLOGIC RESEARCH SAMPLING
52.1. The skin biopsy is performed by the site investigator, or another qualified clinician appointed by the investigator. Skin punch biopsy will be performed under local anesthesia (lidocaine) in the posterior neck according to the Schedule of Activities. Up to two punches will be completed and the skin samples will be processed as described in the PPMI Biologics Manual and shipped to the central biorepository for storage and analysis.
SECTION: BIOLOGIC RESEARCH SAMPLING
52.2. Remaining samples may be used to evaluate other proteins, analytes or potential biomarkers. Participants will not receive any individual results of analysis or testing conducted on the skin samples. Participants will be monitored the day of the procedure for adverse events. Participants will also be contacted by phone 2 to 3 [business/working] days following a skin biopsy to assess for any adverse events.
SECTION: IMAGING
53. Dopamine Transporter SPECT Imaging
 

SECTION: IMAGING
53.1. Participants will undergo dopamine transporter imaging to measure dopamine transporter binding using single photon emission computed tomography (SPECT). All new participants will undergo SPECT imaging at Screening. All new and transitioning participants will also undergo follow up SPECT imaging as indicated in their cohort visit schedule.
 

SECTION: IMAGING
53.2. The SPECT imaging procedure will be performed at the individual sites using DaTscanTM to target the dopamine transporter and all imaging data will be submitted for analysis to the Imaging core. SPECT imaging eligibility will be determined using pre-specified imaging cut-offs. SPECT eligibility result will be made available to the participant’s clinical site.
SECTION: IMAGING
53.3. Women of childbearing potential must have a urine (or serum if required by the site) pregnancy test prior to injection of DaTscanTM. The result must be confirmed as negative prior to proceeding with the injection. Before the DaTscanTM injection, participants will be pre-treated with stable iodine (10 drops of a saturated solution of potassium iodide) to reduce the uptake of DaTscanTM by the thyroid. If the participant is allergic to iodine, then potassium perchlorate 400 mg) can be substituted for potassium iodide. Participants will be injected with up to 5 mCi of DaTscanTM. Within a 4-hour (+/- 30 minute) window following the injection, participants will undergo SPECT imaging for approximately 30 minutes (or up to an hour if the participant moved during scanning).
SECTION: IMAGING
53.4. Participants will be monitored by study personnel for adverse events on the day that a dopamine transporter SPECT scan is obtained. Participants will also be contacted by phone 2 to 3 [business/working] days following the injection/scan to assess adverse events.
SECTION: IMAGING
53.5. The product used to complete the dopamine transporter SPECT scans is being used “offlabel” in the PPMI Clinical study. The imaging result obtained from the scan is not intended to provide information about a clinical diagnosis and will not be shared with participants.
SECTION: IMAGING
54. Magnetic Resonance Imaging (MRI)
 
Participants will undergo an MRI brain scan at the Baseline visit and will also undergo follow up MRI scans as indicated in the visit schedule. At the discretion of the Investigator and Imaging staff, participants who have presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body or any other known contra-indication to MRI may be advised not to complete a Baseline (or follow-up) MRI scan, but these participants may still participate in the study.

SECTION: RISKS TO PARTICIPANTS
55. Blood Sampling

Risks associated with venous blood draw include pain and bruising at the site where the blood is taken. Sometimes people can feel lightheaded or even faint after having blood drawn.
SECTION: RISKS TO PARTICIPANTS
56. MRI

Participants should notify the study doctor if they suffer from claustrophobia because they may become anxious while in the magnetic resonance scanner. The investigator may treat the participant for anxiety if indicated. There may be loud noises such as knocking or hammering that occur while the MRI is being conducted. Participants should also inform the study doctor if they have a pacemaker or metal implants (screws, plates or clips) because this may preclude MR evaluation.
SECTION: RISKS TO PARTICIPANTS
57. SPECT Imaging Using DaTscanTM
SECTION: RISKS TO PARTICIPANTS
57.1. Risks of DaTscanTM: DaTscanTM is administered at radiotracer doses and is not expected to have any pharmacological or toxicological effects. DaTscanTM binds to the dopamine and serotonin transporter. At pharmacologic doses DaTscanTM might be expected to have stimulant-like effects and affect cardiovascular responses. However, in the proposed study the estimated mass dose of DaTscanTM is very low (<30/pmol kg). More than 500,000 doses of the radiotracer have been administered to human participants.
SECTION: RISKS TO PARTICIPANTS
57.2. Iodine: Prior to each injection, participants will be pretreated with Lugol’s (or similar) solution, 10 drops of a saturated solution of potassium iodide, to reduce thyroid uptake of the radioactive agent. Participants may experience a metallic or bitter taste in their mouths from the iodine. Participants with allergies to iodine might get itching, a rash, bloating, severe blood pressure changes (shock), and death if given iodine. Participants who are allergic to iodine may be imaged without Lugol’s or if available may be administered potassium perchlorate rather than Lugol’s.
SECTION: RISKS TO PARTICIPANTS
57.3. In addition to the known risks listed above, these imaging procedures may cause unknown risks to the participant, or a developing embryo or fetus or possible risks to the future offspring of male participants. Female participants of childbearing potential will be asked to have a pregnancy test. Female participants and male participants whose partners become pregnant within 30 days of DaTscanTM injection should report the pregnancy on the Report of Pregnancy data form in EDC within 24 hours of notification of the pregnancy.
SECTION: RISKS TO PARTICIPANTS
58. Lumbar Puncture

The most common risks of a lumbar puncture are pain at the site and a temporary headache usually due to a small amount of CSF leakage around the needle insertion site. Lying down for 30 -60 minutes after the test may make a headache less likely to occur. There is a slight risk of infection because the needle breaks the skin’s surface, providing a possible portal of entry for bacteria. A temporary numbness to the legs or lower back pain may be experienced. There is a small risk of bleeding in the spinal canal. Participants will have blood drawn at the Screening or Baseline visit to test for coagulopathies.
SECTION: RISKS TO PARTICIPANTS
59. Skin Biopsy

Risks associated with performing punch biopsies of the skin include pain and bruising at the site where the biopsy is taken. There is a small risk that the biopsy site may change color. The skin biopsy may leave a scar. There is also a small possibility of infection or bleeding at the biopsy site. Although very rare, it is possible to have an allergic reaction to the local anesthetic (lidocaine) or betadine.
SECTION: RISKS TO PARTICIPANTS
60. Disclosure of Genetic Information

All genetic information will be maintained in a confidential research file. While every effort will be made to maintain confidentiality there is a small risk that information will be disclosed.
SECTION: REFERRALS IN THE CASE OF CLINICALLY RELEVANT FINDINGS
61. If an assessment, lab, or MRI reveals a clinically significant abnormality (e.g., MRI structural lesion, indication of suicidality, depression, or renal impairment on metabolic profile), the participant will be informed of this result and instructed to follow up with his or her primary care physician. Should there be a safety concern warranting a referral for medical or psychiatric follow-up, the Investigator should provide the participant with the appropriate referral as necessary. The sites will follow their standard procedures for clinically urgent and non-urgent medical situations identified during study visits.
SECTION: RETURN OF RESEARCH FINDINGS
62. In addition to the standard of care/clinically relevant results described above, information collected may result in obtaining research findings that could impact a participant’s clinical care choices or decisions due to the extensive clinical and biomarker characterization that participants undergo in PPMI to achieve the goals of this study (for example, genetic results from non-CLIA certified testing, change in research diagnosis). The Investigator will use his/her judgment in determining whether to discuss these findings with the participant.
SECTION: POTENTIAL BENEFITS TO PARTICIPANTS
63. There are no direct anticipated benefits to study participants in this study. However, new information may be generated by the study that will support development of better treatments for Parkinson’s disease.
SECTION: CONCOMITANT MEDICATIONS
64. Use of Concomitant Medications
SECTION: CONCOMITANT MEDICATIONS
64.1. Concomitant medications, including over-the-counter (OTC), dietary supplements (e.g., herbal remedies) or prescriptions, are permitted during the study period, except for the following medications that might interfere with dopamine transporter SPECT imaging which are restricted for 5 half-lives prior to a DaTscanTM injection: alpha methyldopa, methylphenidate, modafinil, amphetamine derivatives and other CNS stimulants.
SECTION: CONCOMITANT MEDICATIONS
64.2. Medications known to be associated with drug induced parkinsonism will not be allowed for 6 months prior to screening and for the duration of the study, dopamine receptor blockers (neuroleptics), metoclopramide and reserpine. All concomitant medications reported at the time of the Screening visit and for the duration of participation are recorded on the study medication logs.
SECTION: CONCOMITANT MEDICATIONS
65. Initiation of PD Medication

It is anticipated that PD participants will not require PD medications for at least 6 months after Baseline. However, PD medications may be initiated at any time after enrollment at the discretion of the participant or treating physician (see Step 43). The medication used is at the discretion of the treating physician. The Investigator will document any new medications or changes in medication at each study visit on the study medication logs.
SECTION: PARTICIPATION IN CLINICAL TRIALS
66. It is understood that individuals may want to participate in therapeutic clinical trials. It is preferred, but not required, that participants who choose to participate in clinical trials of investigational therapeutics, begin their clinical trial following 12 months of participation in PPMI. All participants who do enroll in a clinical trial may remain in the PPMI Clinical study. PPMI will work collaboratively with the clinical trial sponsor to share PPMI study data and encourage clinical trial participants to remain in PPMI Clinical in whatever capacity possible. Contact the Site Management Core for further instruction and to determine whether an in-person PPMI visit may be needed before the participant begins a therapeutic clinical trial. For those studies testing a drug, the Investigator will document on the medication log the study drug dosage, if applicable and known, and, if unknown, will report on the identity of the study drug and dosage after it is unmasked. Other information pertaining to participation in other clinical trials or observational studies may be documented in the PPMI study database.
SECTION: COSTS FOR PARTICIPATION
67. All research travel, assessments and tests will be provided with no cost to the study participant.
SECTION: PAYMENT AND REIMBURSEMENT FOR PARTICIPATION
68. Participants will be paid for completed study visits based on the visit type. Participants who require travel to the clinical site, or incur other costs associated with a study visit, will be reimbursed according to the study reimbursement guidelines. Participants will have the option to receive funds using either a pre-paid card, or direct deposit to a personal account.
SECTION: PARTICIPANT WITHDRAWALS
69. Study participants will be informed during the consent process that they have the right to withdraw from the study at any time without prejudice and may be withdrawn at the Investigator’s or Sponsor’s discretion at any time. Any information that has already been collected prior to the study participant’s withdrawal will not be removed. Participants who withdraw from the PPMI Clinical study might no longer be able to participate in some studies under the PPMI program.
SECTION: ADVERSE EVENTS
70. Adverse Event Reporting Requirements
SECTION: ADVERSE EVENTS
70.1. Site investigators and coordinators will be instructed to assess for adverse events at the study visit when SPECT imaging, lumbar puncture, or skin biopsy is conducted, as well as by telephone 2 to 3 [business/working] days following such activity. Adverse experiences, whether observed by the investigator, or elicited from or volunteered by the participant, should be recorded on the Adverse Event Log. Events occurring outside of the study procedure adverse event reporting period defined above do not require documentation for study purposes (i.e., will not be listed on the Adverse Event Log).
SECTION: ADVERSE EVENTS
70.2. Any adverse event ongoing at the 2 to 3 [business/working] day reporting telephone visit, should be followed until resolution or stabilization. Adverse events reported following a premature withdrawal or conclusion of participation visit should be followed not more than 30 days from last study procedure (i.e., SPECT imaging, lumbar puncture, skin biopsy).
SECTION: ADVERSE EVENTS
70.3. Adverse events will be reported by the site as required by the site’s Institutional Review/Ethics Board and to the Radiation Safety Committee, as applicable.
SECTION: ADVERSE EVENTS
71. Serious Adverse Event Reporting Requirements

Serious adverse events pertaining to SPECT imaging using DaTscanTM, lumbar puncture, or skin biopsy will be reported as follows (see Operations Manual for detailed SAE reporting instructions):
SECTION: ADVERSE EVENTS
71.1. Any serious adverse event occurring within 24 hours following the DaTscanTM injection will be documAdverse Event Definitionsented on the Adverse Event Log and reported to GE Healthcare using PPMI GE Healthcare SAE Form, whether assessed as related to administration of DaTscanTM or not.
SECTION: ADVERSE EVENTS
71.2. Any serious adverse event occurring more than 24 hours following the DaTscanTM injection that is assessed as being related to the DaTscanTM injection will be documented on the Adverse Event Log and reported to GE Healthcare using PPMI GE Healthcare SAE Form.
SECTION: ADVERSE EVENTS
71.3. Any serious adverse event occurring up to 3 days following a lumbar puncture or skin biopsy will be documented on the Adverse Event Log and may result in additional follow up with the site.
SECTION: ADVERSE EVENTS
71.4. The Investigator will comply with his/her local Institutional Review Board (IRB)/Ethics Board, and Radiation Safety Committee (as applicable), regarding the reporting of adverse experiences.
SECTION: ADVERSE EVENTS
72. Adverse Event Definitions
SECTION: ADVERSE EVENTS
72.1. Adverse Events (AE)

An AE is any undesirable experience occurring to a participant during study participation, whether or not considered related to the study procedure.
SECTION: ADVERSE EVENTS
72.2. Serious Adverse Event (SAE)

An SAE is an AE that is fatal or life-threatening, or results in hospitalization, prolongation of hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect. A life-threatening AE is an AE that, in the view of the investigator, places the participant at immediate risk of death from the reaction, as it occurred. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Inpatient admission in the absence of a precipitating, treatment-emergent, clinical adverse event is not participant to immediate reporting. For example:

Admission for treatment of a pre-existing condition not associated with the development of a new adverse event.
Social admission (e.g., participant has no place to sleep).
Protocol-specific admission during a clinical study (e.g., for a procedure required by another study protocol).
Optional admission not associated with a precipitating clinical adverse event (e.g., for elective cosmetic surgery).

Inpatient admission does not include the following:

Emergency Room/Accident and Emergency/Casualty Department visits
Outpatient/same-day/ambulatory procedures
Observation/short-stay units
Rehabilitation facilities
Hospice facilities
Respite care (e.g., caregiver relief)
Skilled nursing facilities
Nursing homes
Custodial care facilities
SECTION: ADVERSE EVENTS
73. Assessing Relationship of Adverse Events

The assessment of the relationship of an AE to the imaging procedure, lumbar puncture, or skin biopsy is a clinical decision based on all available information at the time the event is being documented. The following definitions of the relationship between the AE (including SAEs) and the study procedure should be considered:
SECTION: ADVERSE EVENTS
73.1. Unrelated - No possible relationship
The temporal relationship between study procedure and the adverse event onset/course is unreasonable or incompatible, or a causal relationship to study procedure is implausible.
SECTION: ADVERSE EVENTS
73.2. Unlikely - Not reasonably related, although a causal relationship cannot be ruled out.
While the temporal relationship between study procedure and the adverse event onset/course does not preclude causality, there is a clear alternate cause that is more likely to have caused the adverse event than the study procedure.
SECTION: ADVERSE EVENTS
73.3. Possible - Causal relationship is uncertain
The temporal relationship between study procedure and the adverse event onset/course is reasonable or unknown, and while other potential causes may not exist, a causal relationship to the study procedure does not appear probable.
SECTION: ADVERSE EVENTS
73.4. Probable - High degree of certainty for causal relationship
The temporal relationship between study procedure and the adverse event onset/course is reasonable and other causes have been eliminated or are unlikely.
SECTION: ADVERSE EVENTS
73.5. Definite - Causal relationship is certain
The temporal relationship between study procedure and the adverse event onset/course is reasonable and other causes have been eliminated.
SECTION: ADVERSE EVENTS
74. Assessing Intensity/Severity of Adverse Event

In addition to assessing the relationship of the adverse event to the study procedure, an assessment is required of the intensity (severity) of the event. The following classifications should be used:
SECTION: ADVERSE EVENTS
74.1. Mild:
A mild AE is an AE, usually transient in nature and generally not interfering with normal activities.
SECTION: ADVERSE EVENTS
74.2. Moderate:
A moderate AE is an AE that is sufficiently discomforting to interfere with normal activities.
SECTION: ADVERSE EVENTS
74.3. Severe:
A severe AE is an AE that incapacitates the participant and prevents normal activities.
 

SECTION: SIGNIFICANT STUDY EVENTS
75. There are important events that might occur during a participant’s follow up in the study, such as initiation of PD medication, new clinical diagnosis, an SAE, pregnancy, or death. This information will be captured within the study database and may result in additional follow up with the site. These events are fully described in the Operations Manual.
SECTION: STUDY MONITORING AND SITE MANAGEMENT
76. The PPMI Steering Committee has the responsibility to monitor all procedures for safety, GCP, and regulatory compliance. The study sites will be managed and overseen in an ongoing manner to verify:
SECTION: STUDY MONITORING AND SITE MANAGEMENT
76.1. The rights and well-being of human participants are protected.
SECTION: STUDY MONITORING AND SITE MANAGEMENT
76.2. The reported study data are accurate, complete, and attributable.
SECTION: STUDY MONITORING AND SITE MANAGEMENT
76.3. The conduct of the study follows the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
SECTION: PRIVACY AND CONFIDENTIALITY
77. Privacy of participants will be protected in that each person will have the option to voluntarily choose whether to participate in this study. It is the responsibility of the site Investigator to consider the participant’s privacy and confidentiality when completing study visits and related protocol activities.
SECTION: PRIVACY AND CONFIDENTIALITY
78. The Site Investigator must assure that the confidentiality of participants, including their personal identity and personal medical information, will be maintained at all times. U.S. sites have additional confidentiality obligations to study participants under the Health Insurance Portability and Accountability Act (HIPAA), while European sites have additional obligations under the EU General Data Protection Regulation (GDPR). Participants will be identified by participant ID numbers on data forms and other study materials submitted to the Site Management Core (SMC), the central laboratory, and central biorepository.
SECTION: PRIVACY AND CONFIDENTIALITY
79. The Site Investigator will permit the study monitor or designated SMC representative to review signed informed consent(s) and that portion of the participant’s medical record that is directly related to the study (or provide certified copies of source documentation upon request). This shall include all study relevant documentation including participant medical history to verify eligibility, laboratory test result reports, admission/discharge summaries for hospital admissions occurring while the participant is in the study, and autopsy reports for deaths occurring during the study (when available). In addition, electronic document storage will be maintained within the Florence electronic trial master file.
SECTION: PRIVACY AND CONFIDENTIALITY
80. Identifiable participant information may be stored within this system, which has been validated and deemed compatible with 21 CFR Part 11 requirements. Only study staff requiring access to related study documentation will have permission to view identifiable information.
SECTION: DATA AND SAMPLE SHARING AND STORAGE FOR FUTURE USE
81. Additional data collected for this study will be maintained and stored indefinitely at the study Cores on secure, password protected systems. All study information (data and samples) will be accessed only by those who require access as pertains to the individual’s role on the study. All organizations responsible for data storage and review will observe the highest precautions to ensure data integrity and security.
SECTION: DATA AND SAMPLE SHARING AND STORAGE FOR FUTURE USE
82. Data collected for this study may be transferred and shared across participating PPMI Cores including the Clinical Trials Statistical and Data Management Center (CTSDMC) at the University of Iowa, Indiana University PPMI Cores (Indianapolis, IN), the Site Management Core at the Institute for Neurodegenerative Disorders (New Haven, CT), and the Statistical Core at the University of Iowa (Iowa City, IA) for conducting analyses as pertains to the study including, but not limited to, enrollment, compliance, study outcomes and, in combination from the data received from PPMI Online and PPMI Remote studies, to enable modifications to the predictive prodromal eligibility criteria. All PPMI data will be incorporated into a fully harmonized PPMI database.
SECTION: DATA AND SAMPLE SHARING AND STORAGE FOR FUTURE USE
83. All data obtained during the conduct of PPMI Clinical will be sent to the Laboratory of Neuro Imaging (LONI) in Los Angeles, California to be stored indefinitely for research purposes. Research data will be made available to researchers to conduct analyses related to PD and other disorders. Researchers will be required to comply with the PPMI data agreement to receive data. All personally identifiable information will be removed before it is shared outside the study.
SECTION: DATA AND SAMPLE SHARING AND STORAGE FOR FUTURE USE
84. Research biosamples will be shipped and stored indefinitely for research purposes at the Biorepository Cores at Indiana University School of Medicine, BioRep in Milan, Italy and Tel Aviv Sourasky Medical Center in Tel Aviv, Israel. Research specimens will be made available to researchers to conduct analyses related to PD and other disorders through an application process to the Biospecimen Review Committee (BRC). All personally identifiable information will be removed before it is shared outside the study.
SECTION: ANALYSIS PLAN
85. The overall goal of PPMI is to identify markers of disease progression to inform clinical trials of therapies to reduce progression of PD disability. Correspondingly, all primary and secondary analyses of the PPMI data will focus on this goal. However, due to the rich nature of data collected as part of this study, many additional exploratory analyses will be examined throughout the study – both within and outside of the primary study steering committee.
SECTION: ANALYSIS PLAN
86. Throughout the course of the study, analyses will be periodically updated to examine and compare baseline characteristics among the various subsets enrolled into the study. Continuous variables will be examined using a t-test and dichotomous variables will be examined using a chi-square test. Appropriate assumptions will be assessed for each comparison and necessary adjustments (i.e., transformations) will be made prior to analysis.
SECTION: ANALYSIS PLAN
87. Primary Objectives
Comparison of progression biomarkers among cohorts/subsets
SECTION: ANALYSIS PLAN
87.1. Use clinical and biological data to estimate the mean rates of change and variability around the mean of clinical, digital, imaging, biological, and genetic outcomes in study participants with PD diagnosis [including patients with a LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1)] and individuals with prodromal Parkinson’s disease [including individuals with RBD, olfactory loss, LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1)] and/or other risk factors for PD with and without DAT deficit and in healthy participants.
SECTION: ANALYSIS PLAN
87.2. Due to the large number of progression endpoints possible for consideration, a substantial number of analyses will be conducted to examine the change and variability over time. These analyses will include standard logistic, linear, and longitudinal models, and many other proposed approaches for assessing these data. Primary interest will focus on wellknown and accepted measures of disease progression (such as the MDS-UPDRS). But, an examination and potential development of novel progression endpoints to better characterize disease progression over time in this heterogeneous cohort will be considered.
SECTION: ANALYSIS PLAN
88. Examination of PD subsets

Analyses will also be conducted to assess whether there are subgroup differences observed with respect to disease progression. Analyses will confirm existing and identify novel clinical, digital, imaging, biologic, and genetic PD progression markers to identify quantitative individual measures or combinations of measures that demonstrate optimum interval change in study participants with PD diagnosis [including patients with a LRRK2, GBA, SNCA or rare genetic variants (such as Parkin or Pink1)] and individuals with prodromal Parkinson’s disease [including individuals with RBD, olfactory loss, LRRK2, GBA, or rare genetic variants (such as Parkin or Pink1)] and/or other risk factors for PD with and without DAT deficit in comparison to healthy controls or in subsets of study participants with PD diagnosis or prodromal PD defined by baseline assessments, progression milestones and/or rate of clinical, digital, imaging, biologic, and genetic change, or other measures.
SECTION: ANALYSIS PLAN
89. Analysis of prodromal participants phenoconversion

Evaluate the probability of phenoconversion for PD for individuals with prodromal PD enrolled in the prodromal cohorts [including individuals with RBD, olfactory loss, LRRK2, GBA, SNCA, or rate genetic variants (such as Parkin or Pink1)] and/or other risk factors for PD with and without DAT deficit. This analysis will involve estimating the number and percentage of prodromal participants that meet criteria for phenoconversion at a number of observed time points. For each period of time, the percentage and a 95% confidence interval will be reported.
SECTION: ANALYSIS PLAN
90. Secondary Objectives
SECTION: ANALYSIS PLAN
90.1. Ancillary biomarker studies

Conduct preliminary clinical, digital, imaging, biologic, and genetic markers verification studies on promising biological markers in study subsets using stored collected samples. A series of ancillary analyses will be conducted to verify known and novel proposed PD biomarkers. These studies will vary substantially depending on the type of marker. But, as much as possible, the methods and analysis plans for all verification studies will be reviewed centrally by the PPMI steering committee in advance of implementation.
SECTION: ANALYSIS PLAN
90.2. Compare genetic and idiopathic PD

Compare biomarker signatures for study participants with PD diagnosis without known genetic variants to those with known genetic variant [including LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1)]. These analyses will initially involve a high-level comparison of whether PD progression over time differs among those with and without a known genetic variant. Subsequent analyses will be implemented in much the same way as above, with the exception that models will implicitly assume and examine potential interactions between presence or absence of a known genetic variant and each of the potential progression markers considered in the various models.
SECTION: ANALYSIS PLAN
90.3. Compare Prodromal and PD

Compare biomarker signatures for study participants with PD diagnoses to individuals with prodromal PD enrolled in the prodromal cohorts [including individuals with RBD, olfactory loss, LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1)] and/or other risk factors for PD with and without DAT deficit and between prodromal participants who phenoconvert and those that have not phenoconverted.
SECTION: ANALYSIS PLAN
90.4. Model Prodromal progression and predictors of phenoconversion

Develop and test risk paradigms to establish the sequence of early prodromal events (clinical, imaging, biologic changes) in individuals with prodromal PD enrolled in the prodromal cohorts [including individuals with RBD, olfactory loss, LRRK2, GBA, SNCA, or rare genetic variants (such as Parkin or Pink1) and/or other risk factors for PD with and without DAT deficit] including testing early signal of risk in the associated PPMI Online and PPMI Remote studies.