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Study to Identify Clinical, Imaging and Biologic Markers of Parkinson Disease Progression (PPMI)

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ClinicalTrials.gov Identifier: NCT01141023
Recruitment Status : Recruiting
First Posted : June 10, 2010
Last Update Posted : August 15, 2019
Sponsor:
Collaborator:
Institute for Neurodegenerative Disorders
Information provided by (Responsible Party):
Ken Marek, MD, Michael J. Fox Foundation for Parkinson's Research

Tracking Information
First Submitted Date  ICMJE June 8, 2010
First Posted Date  ICMJE June 10, 2010
Last Update Posted Date August 15, 2019
Study Start Date  ICMJE June 2010
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2019)
Mean Rates of Change [ Time Frame: Baseline to 156 months ]
The mean rates of change and the variability around the mean of clinical, imaging and biomic outcomes in early PD patients, and where appropriate the comparison of these rates between PD patient subsets and between various subsets (including, but not limited to: PD vs. healthy subjects, PD vs. SWEDD, PD vs. prodromal, PD with and without LRRK2, GBA or SNCA mutation, unaffected LRRK2, GBA or SNCA mutation carriers vs. healthy controls) at study intervals ranging from 3 months to 36 months. Specific examples of outcomes include MDS-UPDRS, dopamine transporter imaging striatal uptake, vesicular monoamine transporter type-2 uptake, and serum and CSF alpha-synuclein. PD patient subsets may be defined by baseline assessments, genetic mutations, progression milestones and/or rate of clinical, imaging, or biomic change.
Original Primary Outcome Measures  ICMJE
 (submitted: June 8, 2010)
The mean rates of change and the variability around the mean of clinical, imaging and biomic outcomes in early PD patients, and where appropriate the comparison of these rates between PD patient subsets and between PD and healthy subjects. [ Time Frame: Study intervals from 3 months - 36 months ]
Specific examples of outcomes include MDS-UPDRS, DAT striatal uptake, and serum and CSF alpha-synuclein. PD patient subsets may be defined by baseline assessments, progression milestones and/or rate of clinical, imaging, or biomic change.
Change History Complete list of historical versions of study NCT01141023 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2019)
  • Comparison between Rates of Change [ Time Frame: Study intervals ranging from 3 months to 156 months ]
    Comparison between the rates of change in the mean of clinical, imaging and biomic outcomes in various subsets (including, but not limited to: early PD vs. healthy subjects, PD vs. SWEDD, PD vs. prodromal, PD with and without LRRK2, GBA or SNCA mutation, unaffected LRRK2, GBA or SNCA mutation vs. healthy controls)
  • Prevalence of measures of clinical, imaging and biomic outcomes in various subsets ( [ Time Frame: study intervals ranging from baseline to 156 months. ]
    Including, but not limited to: early PD patients, healthy subjects, PD vs SWEDDs, PD vs prodromal, PD with and without LRRK2, GBA or SNCA mutation, unaffected LRRK2, GBA or SNCA mutation carriers vs. healthy subjects.
  • Predictive Value [ Time Frame: Baseline to 156 months ]
    To establish the predictive value of early clinical non-motor features, baseline imaging and biomic outcomes for future course of disease.
  • To examine the proportion of SWEDD subjects that have a change in their clinical management at 24 months [ Time Frame: Baseline to 156 Months ]
    SWEDD Clinical Diagnosis and Management Questionnaire.
  • Exploratory Analysis [ Time Frame: Baseline to 156 months ]
    Exploratory analysis to estimate the percentage of Prodromal subjects with one or more risk characteristics [hyposmia (<10th percentile for age and gender), RBD, or LRRK2, GBA or SNCA genetic mutation, and baseline DaTSCAN binding showing minimal to moderate DAT deficit] that phenoconvert to PD within 2 years, and an exploratory analysis to examine whether the baseline DaTSCAN binding or progression of clinical, imaging, or biospecimen markers may predict those subjects likely to phenoconvert.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2010)
  • Correlations between the rates of change in the mean of clinical, imaging and biomic outcomes in early PD patient subsets and between PD and healthy subjects [ Time Frame: Study Intervals from 3 months to 36 months ]
  • Prevalence of measures of clinical, imaging and biomic outcomes in early PD patients and healthy subjects. [ Time Frame: from baseline to 36 months. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Identify Clinical, Imaging and Biologic Markers of Parkinson Disease Progression
Official Title  ICMJE The Parkinson's Progression Markers Initiative (PPMI)
Brief Summary

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

The primary objective of this study is to identify clinical, imaging and biologic markers of PD progression for use in clinical trials of disease-modifying therapies.

Detailed Description

Amendment 14 - 26-Mar-2018 Revised to reflect the implementation of PPMI Wearables and Sensor Study Companion Protocol

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

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

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

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

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

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

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

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

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

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

Amendment 4 - 30-Mar-2012 Addition of 18F-AV-133 VMAT-2 PET Imaging for participating U.S. sites and Australia. (Refer to 18F-AV-13-PPMI companion protocol).

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

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

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

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

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

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Parkinson Disease
Intervention  ICMJE Drug: DaTscan
Other Name: Ioflupane
Study Arms  ICMJE Experimental: Datscan SPECT Imaging
Subjects will b injected with 3-5 mCi of dopamine transporter. Within a 4 hour (+/- 30 minutes) window following the injection, subjects will undergo SPECT imaging on the camera.
Intervention: Drug: DaTscan
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 12, 2012)
680
Original Estimated Enrollment  ICMJE
 (submitted: June 8, 2010)
600
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Parkinson Disease (PD) Subjects:

  • A diagnosis of Parkinson disease for 2 years or less at Screening.
  • Confirmation from imaging core that screening DAT scan is consistent with dopamine transporter deficit, or if applicable a VMAT-2 PET scan consistent with vesicular monoamine transporter deficit.
  • Not expected to require PD medication with at least 6 months from Baseline.
  • Male or female age 30 years or older at time of PD diagnosis.

Healthy Control (HC) Subjects:

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

Exclusion Criteria:

Parkinson Disease (PD) Subjects:

  • Currently taking levodopa, dopamine agonists, MAO-B inhibitors, amantadine or other PD medication.
  • Has taken levodopa, dopamine agonists, MAO-B inhibitors or amantadine within 60 days of Baseline.
  • Has taken levodopa or dopamine agonists prior to Baseline for more than a total of 60 days.
  • Received any of the following drugs that might interfere with DAT imaging: Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or amphetamine derivative, within 6 months of Screening.
  • Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.

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

  • Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
  • Use of investigational drugs within 60 days prior to Baseline (dietary supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme Q10).

Healthy Control (HC) Subjects:

  • Current or active neurological disorder.
  • First degree relative with idiopathic PD (parent, sibling, child).
  • MoCA score < 26.
  • Received any of the following drugs that might interfere with DAT imaging: Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or amphetamine derivative, within 6 months of Screening.

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

  • Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.
  • Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
  • Use of other investigational drugs within 60 days prior to baseline (dietary supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme Q10).

SWEDD Subjects:

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

Prodromal Subjects:

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

Hyposmia:

  1. Male or female age 60 years or older
  2. Confirmation from olfactory core that olfaction as determined by UPSIT is at or below the 10th percentile by age and gender

REM Behavior Disorder (RBD):

  1. Male or female age 60 years or older
  2. Confirmation from sleep core that subject's Polysomnography (PSG) meets criteria for RBD

LRRK2:

  1. Male or female age 60 years or older
  2. Written confirmation or documentation from testing facility that the individual is LRRK2 mutation positive 4.2.7.2. Confirmation from imaging core that screening dopamine transporter SPECT scan is read as eligible (see below). About 80 subjects will have a range of DAT deficit similar to subjects with early PD (mild to moderate DAT deficit). About 20 subjects will be selected with no DAT deficit or minimal DAT deficit similar in age, gender, and risk profile to those with mild to moderate DAT deficit. 4.2.7.3. Ability to provide written informed consent in accordance with Good Clinical Practice (GCP), International Conference on Harmonization (ICH), and local regulations. 4.2.7.4. Willing and able to comply with scheduled visits, required study procedures and laboratory tests. 4.2.7.5. Women may not be pregnant, lactating or planning pregnancy during the course of the study. Includes a negative urine pregnancy test on day of screening scan prior to injection (DaTSCAN).

Exclusion Criteria (Prodromal Subjects)

  1. Current or active clinically significant neurological disorder or psychiatric disorder (in the opinion of the Investigator).
  2. GDS score greater than or equal to 10 (GDS score of 5 - 9 requires Investigator discretion to enter study).
  3. STAI Form Y-1 greater than or equal to 54 requires Investigator discretion to enter study.
  4. A clinical diagnosis of dementia63 as determined by the investigator (Appendix 1).
  5. A clinical diagnosis of Parkinson disease at the Screening visit as determined by the Investigator.
  6. Received any of the following drugs that might interfere with dopamine transporter SPECT imaging: Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or amphetamine derivative, within 6 months of Screening.
  7. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.
  8. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia.
  9. Any other medical or psychiatric condition or lab abnormality, which in the opinion of the investigator might preclude participation.
  10. Use of investigational drugs or devices within 60 days prior to Baseline (dietary supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme Q10).
  11. Previously obtained MRI scan with evidence of clinically significant neurological disorder (in the opinion of the Investigator).

Genetic Cohort: Parkinson Disease Subjects - Inclusion:

  1. Patients must have at least two of the following: resting tremor, bradykinesia, rigidity (must have either resting remor or bradykinesia) or either asymmetric resting tremor or asymmetric bradykinesia.
  2. A diagnosis of Parkinson Disease for 7 years or less at screening.
  3. Hoehn and Yahr state <4 at baseline
  4. Male or female age 18 years or older
  5. Willingness to undergo genetic testing and to be informed of genetic testing results.
  6. Confirmation of mutation in LRRK2, GBA or SNCA
  7. For subjects taking any drugs that might interfere with dopamine transporter SPECT imaging (Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine or amphetamine derivative must be willing and able from a medical standpoint to hold the medication for at least 5 half-lives prior to screening DatSCAN(TM) imaging.

Exclusion:

  1. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude safe completion of the lumbar puncture.
  2. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis or clinically significant coagulopathy or thrombocytopenia.

Genetic cohort - Unaffected Individuals

Inclusion:

  1. Male or female age 45 years or older at baseline with LRRK2 or GBA mutation and/or first degree relative with a LRRK2 or GBA mutation or
  2. Male or female age 30 years or older at baseline with a SNCA mutation and/or a first degree relative with a SNCA mutation.
  3. Unaffected subjects at high risk of LRRK2, GBA or SNCA mutation due to first degree relative with a LRRK2, GBA or SNCA mutation may choose either to be informed of the results or remain unaware of the results.
  4. Unaffected subjects from an ethnic or geographic group knkown to have relatively high risk of LRRK2, GBA or SNCA mutation such as people of Ashkenazi Jewish or Basques descent) and who have a family member (either alive or deceased) who has/had PD must be willing to be informed of their own testing results.
  5. Willingness to undergo genetic testing
  6. For subjects taking any of the following drugs that might interfere with dopamine transporter SPECT imaging (neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine or amphetamine derivative) must be willing and able from a medical standpoint to hold the medication for at least 5 half-lives prior to DatSCAN imaging.

Exclusion:

  1. A clinical diagnosis of PD
  2. Current treatment with anticoagulants (e.g. coumadin, heparin) that might preclude safe completion of the lumbar puncture.
  3. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis or clinically significant coagulopathy or thrombocytopenia.

Genetic Registry - Inclusion:

  1. Individual with a LRRK2, GBA or SNCA mutation and/or a first degree relative with a LRRK2, GBA or SNCA mutation.
  2. Male or female age 18 years or older
  3. Willingness to undergo genetic testing, but may choose either to be informed of the results or remain unaware of the results.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Australia,   Austria,   France,   Germany,   Greece,   Israel,   Italy,   Norway,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01141023
Other Study ID Numbers  ICMJE PPMI-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ken Marek, MD, Michael J. Fox Foundation for Parkinson's Research
Study Sponsor  ICMJE Ken Marek, MD
Collaborators  ICMJE Institute for Neurodegenerative Disorders
Investigators  ICMJE
Study Chair: Kenneth L Marek, MD Institute for Neurodegenerative Disorders
Study Director: John Q. Trojanowski, MD, PhD University of Pennsylvania
Study Director: Arthur W. Toga, PhD University of California, Los Angeles
Study Director: Tatiana Froud, PhD Indiana University
Study Director: Karl Kieburtz, MD Clinical Trials Coordination Center
Study Director: Andrew Singleton, PhD Laboratory of Neurogenetics; National Institute on Aging NIH
Study Director: John P Seibyl, MD Institute for Neurodegenerative Disorders
Study Director: Christopher Coffey, PhD Clinical Trials Statistical and Data Management Center, University of Iowa
PRS Account Michael J. Fox Foundation for Parkinson's Research
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP