Evaluating dopamine transporter imaging as an enrichment biomarker in a phase 2 Parkinson's disease trial

R Matthew Hutchison, Karleyton C Evans, Tara Fox, Minhua Yang, Jerome Barakos, Barry J Bedell, Jesse M Cedarbaum, Miroslaw Brys, Andrew Siderowf, Anthony E Lang, R Matthew Hutchison, Karleyton C Evans, Tara Fox, Minhua Yang, Jerome Barakos, Barry J Bedell, Jesse M Cedarbaum, Miroslaw Brys, Andrew Siderowf, Anthony E Lang

Abstract

Background: Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can quantify the functional integrity of the dopaminergic nerve terminals and has been suggested as an imaging modality to verify the clinical diagnosis of Parkinson's disease (PD). Depending on the stage of progression, approximately 5-15% of participants clinically diagnosed with idiopathic PD have been observed in previous studies to have normal DaT-SPECT patterns. However, the utility of DaT-SPECT in enhancing early PD participant selection in a global, multicenter clinical trial of a potentially disease-modifying therapy is not well understood.

Methods: The SPARK clinical trial was a phase 2 trial of cinpanemab, a monoclonal antibody against alpha-synuclein, in participants with early PD. DaT-SPECT was performed at screening to select participants with DaT-SPECT patterns consistent with degenerative parkinsonism. Acquisition was harmonised across 82 sites. Images were reconstructed and qualitatively read at a central laboratory by blinded neuroradiologists for inclusion prior to automated quantitative analysis.

Results: In total, 482 unique participants were screened between January 2018 and May 2019; 3.8% (15/398) of imaged participants were excluded owing to negative DaT-SPECT findings (i.e., scans without evidence of dopaminergic deficit [SWEDD]).

Conclusion: A smaller proportion of SPARK participants were excluded owing to SWEDD status upon DaT-SPECT screening than has been reported in prior studies. Further research is needed to understand the reasons for the low SWEDD rate in this study and whether these results are generalisable to future studies. If supported, the radiation risks, imaging costs, and operational burden of DaT-SPECT for enrichment may be mitigated by clinical assessment and other study design aspects.

Trial registration: ClinicalTrials.gov identifier: NCT03318523 . Date submitted: October 19, 2017. First Posted: October 24, 2017.

Keywords: Biomarker; Dopamine transporter; Parkinson’s disease; SPECT; SWEDD.

Conflict of interest statement

R. M. Hutchison, K. C. Evans, T. Fox, and M. Yang are and/or have been employees of and own stock or have stock options, or both, in Biogen. J. M. Cedarbaum and M. Brys were employees of Biogen while completing this work and may own Biogen stock. B. J. Bedell has received compensation and shares from Biospective. The other authors have no relevant disclosures to declare.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Quantitative evaluation of DaT-SPECT striatal binding ratio (SBR). aWhole putamen SBR, b most affected putamen SBR, and c demographically indexed most affected putamen SBR of participants in SPARK categorised by qualitative visual assessment as “abnormal” or “normal.” Demographic indexing normalises metrics to published normal SBR values based on age and sex [42]. Red cross indicates the mean value

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