Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials

John T O'Brien, Wolfgang H Oertel, Ian G McKeith, Donald G Grosset, Zuzana Walker, Klaus Tatsch, Eduardo Tolosa, Paul F Sherwin, Igor D Grachev, John T O'Brien, Wolfgang H Oertel, Ian G McKeith, Donald G Grosset, Zuzana Walker, Klaus Tatsch, Eduardo Tolosa, Paul F Sherwin, Igor D Grachev

Abstract

Objectives: To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane ((123)I)) to detect or exclude a striatal dopaminergic deficit disorder (SDDD), such as parkinsonian syndrome and dementia with Lewy bodies.

Design: Pooled analysis of three phase 3 and one phase 4 clinical trials. These four trials were selected because they were the four studies used for the US new drug application to the Food and Drug Administration (FDA).

Setting: Multicentre, open-label, non-randomised.

Participants: Patients with either a movement disorder or dementia, and healthy volunteers.

Interventions: Ioflupane ((123)I) was administered.

Outcome measures: Images were assessed by panels of 3-5 blinded experts and/or on-site nuclear medicine physicians, classified as normal or abnormal and compared with clinical diagnosis (reference standard) to determine sensitivity and specificity.

Results: Pooling the four studies, 928 participants were enrolled, 849 were dosed and 764 completed their study. Across all studies, when images were assessed by on-site readers, ioflupane ((123)I) diagnostic effectiveness had an overall (95% CI) sensitivity of 91.9% (88.7% to 94.5%) and specificity of 83.6% (78.7% to 87.9%). When reads were conducted blindly by a panel of independent experts, the overall sensitivity was 88.7% (86.8% to 90.4%) and specificity was 91.2% (89.0% to 93.0%).

Conclusions: In this pooled analysis, the visual assessment of ioflupane ((123)I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane ((123)I) imaging has the potential to improve diagnostic accuracy in patients with signs and symptoms of a movement disorder and/or dementia.

Trial registration number: NCT00209456.

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Figures

Figure 1
Figure 1
Participant disposition. AE, adverse event; ITD, intent to diagnose; PP, per protocol.
Figure 2
Figure 2
Summary of clinical diagnosis (per reference clinical standard) by study. (A) ITD population. (B) PP population. AD, Alzheimer's disease; DLB, dementia with Lewy bodies; ET, essential tremor; ITD, intent to diagnose; PP, per protocol; PS, parkinsonian syndrome; SDD, striatal dopaminergic deficit.
Figure 3
Figure 3
Summary of sensitivity (PPA) and specificity (NPA) by expert clinical diagnosis—mean of blind reads. (A) ITD population—summary results calculated across all studies and readers at baseline. DLB is calculated based on probable DLB versus non-DLB. Total is calculated based on SDDD present versus SDDD absent. (B) ITD population—DLB at month 12 calculated for all readers in study PDT301. PS at month 18 and 36 calculated for all readers in study PDT304. (C) PP population—summary results calculated across all studies and readers at baseline. DLB is calculated based on probable DLB versus non-DLB. Total is calculated based on SDDD present versus SDDD absent. (D) PP population—DLB at month 12 calculated for all readers in study PDT301. PS at month 18 and 36 calculated for all readers in study PDT304. DLB, dementia with Lewy bodies; ITD, intent to diagnose; NPA, negative per cent agreement; PP, per protocol; PPA, positive per cent agreement; PS, parkinsonian syndrome; SDDD, striatal dopaminergic deficit disorder.
Figure 4
Figure 4
Summary of sensitivity (PPA) and specificity (NPA) by expert clinical diagnosis—on-site institutional reads. (A) ITD population—summary results calculated across all studies and time points. For PDT301, month 12 reference clinical diagnosis was used in this analysis. DLB is calculated based on probable DLB versus non-DLB. Total is calculated based on SDDD present versus SDDD absent. (B) ITD population—DLB at month 12 calculated for on-site readers in study PDT301. PS at month 18 and 36 calculated for on-site readers in study PDT304. (C) PP population—summary results calculated across all studies and time points. For PDT301, month 12 reference clinical diagnosis was used in this analysis. DLB is calculated based on probable DLB versus non-DLB. Total is calculated based on SDDD present versus SDDD absent. (D) PP population—DLB at month 12 calculated for on-site readers in study PDT301. PS at month 18 and 36 calculated for on-site readers in study PDT304. DLB, dementia with Lewy bodies; ITD, intent to diagnose; NPA, negative per cent agreement; PP, per protocol; PPA, positive per cent agreement; PS, parkinsonian syndrome; SDDD, striatal dopaminergic deficit disorder.

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