TOLEDO

Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO)

Why was the TOLEDO study needed?

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Over time, motor fluctuations usually worsen, leading to long and troublesome periods of immobility and non-motor symptoms. Attempts to control motor fluctuations with oral medication can lead to disabling dyskinesia.15

Although the efficacy of APO-go® PUMP in Parkinson’s disease patients with advanced motor fluctuations is well established in clinical practice, the lack of evidence from Level 1 (randomised, controlled) studies has limited its place in evidence based reviews and guidelines.15

Please click on the following link to access the online publication – Katzenschlager R, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749–759. Published online at: https://doi.org/10.1016/S1474-4422(18)30239-4.

Study design

TOLEDO was a randomised, placebo-controlled, double-blind, multicentre trial including 107 patients at 23 European hospitals. Patients had been diagnosed with Parkinson’s disease for more than 3 years, had motor fluctuations not adequately controlled by medical treatment and were optimised on oral/transdermal medications as judged by the investigator.15

How was the apomorphine infusion initiated in the TOLEDO study?

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Efficacy overview

The TOLEDO study had two pre-specified endpoints, but also included a number of post-hoc analyses examining time patients spent ‘ON’ or ‘OFF’, with and without dyskinesias.15

 

Mean change in various motor states of Parkinson’s disease between baseline and week 1215

Significant reduction in ‘OFF’ time vs. placebo

The primary efficacy endpoint in TOLEDO was the mean change in ‘OFF’ time (derived from patients’ diaries) from baseline to the week 12 visit. APO-go® PUMP significantly reduced ‘OFF’ time from baseline by 2.47 hours per day vs. 0.58 hours per day for the placebo group (treatment difference –1·89 h per day; p=0·0025).15

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Change from baseline to week 12 in ‘OFF’ time*15

*Last observation carried forward: each point is the mean of the values for the two consecutive days before the visit

Adapted from Katzenschlager et al. 2018.

What were the primary efficacy results in the TOLEDO study?

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Significantly more good ‘ON’ time vs. placebo

Compared with placebo, APO-go® PUMP significantly increased on time without troublesome dyskinesia by 1.97 hours a day (p=0.0008). Absolute mean change was 2.77 h per day (SD 3·26) in the apomorphine group and 0·80 h per day (2·93) in the placebo group.15

Change from baseline to week 12 in time spent on without troublesome dyskinesia15

Patient Global Impression of Change (PGIC)

Patient-perceived outcomes are becoming increasingly important in clinical trial reporting and can provide a good indication of quality of life (QoL) improvements, alongside QoL measures.15

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In the TOLEDO study, significantly more APO-go® PUMP patients reported improvements in PGIC vs. placebo. At Week 12, 34 (71%) of 48 patients in the APO-go® PUMP group thought that their general health state had improved compared with 9 (18%) of 51 patients in the placebo group.15

PGIC from baseline to Week 12

What added value does the PGIC data from the TOLEDO study provide?

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Oral levodopa-equivalent dose (LED)

Open-label studies and clinical experience have previously demonstrated APO-go® PUMP can allow for reductions in levodopa dose and/or LED, however this had not yet been proven in controlled trials.

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Mean oral levodopa dose was reduced during the study in both groups, however the difference between the study groups was not significant (-113.5mg; p=0.0615).15

The reduction in oral LED between baseline and Week 12 was significantly greater in the APO-go® PUMP group vs. the placebo group (p=0.0014), and this difference was significant at all visits from Week 4.15

Mean change in levodopa-equivalent dose from baseline to Week 12*15

*Analysis excludes as-needed use and missing data from three sites.

Error bars indicate 95% confidence intervals.

Key safety data

The TOLEDO study demonstrates the tolerability and consistency of adverse events associated with APO-go® PUMP therapy. No unexpected safety signals were observed during TOLEDO and most adverse events were to moderate in intensity.15

The most commonly occurring adverse events (≥5%) in the APO-go® PUMP safety group in TOLEDO were:15

  • Skin nodules at infusion site (44%)
  • Nausea (22%)
  • Somnolence (22%)
  • Erythema at infusion site (17%)
  • Dyskinesia (15%)
  • Headache (13%)
  • Insomnia (11%)

Six patients (11%), all in the apomorphine group, had an adverse event that led to study withdrawal. Three patients withdrew because of serious adverse events.15

Click the button below for full safety information on APO-go® PUMP, or see the summary of product characteristics available at the foot of each page.

Conclusion

TOLEDO provides high-level evidence that APO-go® PUMP leads to a pronounced reduction in ‘OFF’ time, which is associated with an increase in good ‘ON’ time and marked reduction in levodopa-equivalent dose. Patients in the study also rated themselves significantly better on APO-go® compared to placebo, demonstrating the clinically meaningful benefits from the patient’s perspective.17

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  2. 2. Parkinson’s UK. Non-motor Symptoms of Parkinson’s. Available at: https://www.parkinsons.org.uk/information-and-support/non-motor-symptoms-parkinsons. Accessed November 2019.
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  8. 8. Lundqvist C. Neuropsychiatr Dis Treat. 2007;3(3):335–348.
  9. 9. Obeso JA, et al. Neurology. 2000;55(4):S13–S20.
  10. 10. Sujith O K, Lane C. Ther Adv Neurol Disord. 2009;2(2): 105–113.
  11. 11. Xie C-L, et al. Sci Rep. 2014;4:6027. DOI: 10.1038/srep06027.
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  13. 13. Pfeiffer RF, et al. Parkinsonism Relat Disord. 2007;13:93–100.
  14. 14. Merello M, et al. Clin Neuropharmacol. 1997;20(2):165–67.
  15. 15. Katzenschlager R, et al. Lancet Neurol. 2018;17(9):749–759.

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