Objective: Evaluate dopaminergic imaging DAT-SPECT as an enrichment strategy to avoid inclusion of participants with scans without evidence of dopaminergic deficit (SWEDD) in a Phase II clinical trial testing a potential disease-modifying therapy for Parkinson’s Disease (PD)

Background: Prior studies have shown that up to 15% of individuals diagnosed with PD do not demonstrate nigrostriatal denervation when assessed by dopamine transporter imaging. SWEDD individuals do not progress on clinical motor symptoms[1][2], as they potentially do not have PD. Their identification during the screening period in clinical trials for PD is thus key to prevent their inclusion.
We describe the use of DAT-SPECT to exclude SWEDDs during the screening for the Phase II PASADENA trial.

Method: In PASADENA, DAT-SPECT scans of clinically diagnosed PD patients were centrally evaluated by at least two qualified readers for visual evidence of dopaminergic deficits. A binary classification determined an individual’s SWEDD status. Using t-tests, we compared DAT-SPECT semi-quantitative results of striatal binding ratio (SBR), MDS-UPDRS and diffusion MRI between SWEDD participants and participants with abnormal DAT-SPECT.

Results: Overall 28 out of 344 (8%) screened patients’ scans were classified as SWEDDs by visual DAT-SPECT assessment and therefore excluded from randomization. SWEDD participants showed higher DAT-SPECT SBR (M±SD: 2.3±0.6) compared to participants with abnormal DAT (1.5±0.4; p < .01). SWEDD participants scored lower on MDS-UPDRS (3.1±3.4 for part II; 12.9±6.8 for part III) compared to participants with abnormal DAT-SPECT (5.3±4.1, p = .01 for part II; 20.9±9.6, p < .001 for part III).
On diffusion MRI, SWEDD participants showed higher fractional anisotropy in the putamen (left: 0.28±0.02, right: 0.29±0.03) compared to those with abnormal DAT-SPECT (left: 0.27±0.03, p = .01; right: 0.27±0.03, p = .02). SWEDD participants also demonstrated lower mean diffusivity in the substantia nigra (left: 0.80±0.07; right: 0.79±0.06) compared to participants with abnormal DAT (left: 0.84±0.14, p = .02; right: 0.83±0.12, p < .01).

Conclusion: The prevalence of SWEDD individuals during the screening for PASADENA (8%) and difference of clinical and imaging characteristics compared to participants with abnormal DAT-SPECT support the use of DAT-SPECT imaging as an enrichment biomarker for clinical trials in early PD.

References: 1 Lee, Jeong Won, Yoo Sung Song, Hyeyun Kim, Bon D. Ku, and Won Woo Lee. “Patients with Scans without Evidence of Dopaminergic Deficit (SWEDD) Do Not Have Early Parkinson’s Disease: Analysis of the PPMI Data.” PLOS ONE 16, no. 2 (February 10, 2021): e0246881. https://doi.org/10.1371/journal.pone.0246881.
2 Marek, Kenneth, John Seibyl, Shirley Eberly, David Oakes, Ira Shoulson, Anthony E. Lang, Chris Hyson, and Danna Jennings. “Longitudinal Follow-up of SWEDD Subjects in the PRECEPT Study.” Neurology 82, no. 20 (2014): 1791–97. https://doi.org/10.1212/WNL.0000000000000424.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-use-of-dat-spect-as-an-enrichment-biomarker-to-determine-eligibility-for-the-phase-2-clinical-trial-pasadena/