Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study

Abstract

The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP). Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO. Results: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of − 3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515). Conclusions: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.

Early factors for predicting discontinuation to subcutaneous Apomorphine infusion in Parkinson's disease: A prospective analysis of the Thai Apomorphine Registry

“…A recent randomized controlled trial confirmed the significant benefit of CSAI in off hours reduction without any unexpected safety events, compared to a placebo [1]. Observational studies have also reported long-term benefits of CSAI lasting up to 10 years following treatment [3][4][5]. Compared to other device-aided therapies, including levodopa-carbidopa intestinal gel infusion and deep brain stimulation, CSAI is the least invasive drug administration procedure and is easily reversible, whereas the other two options require further surgery for reversal [6].…”

Continuous Subcutaneous Apomorphine Infusion before Subthalamic Deep Brain Stimulation: A Prospective, Comparative Study in 20 Patients

“…However, the level of scientific evidence supporting each of these treatments differs. While several prospective, randomised, and multicentre clinical trials support the use of STN-DBS, only one randomised, double-blind clinical trial, the TOLEDO study 1,2 has been undertaken with APO 1,2 . Despite its long-standing use, many studies that support the use of APO are retrospective and with small sample sizes [3][4][5][6][7][8][9][10] .…”

“…14 with some modifications: (1) advanced stage PD, (2) disease duration over 5 years, (3) reduction in Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores over 50% after levodopa or apomorphine challenge test, (4) age below 71 years, (5) magnetic resonance imaging with no significant vascular damage or structural abnormalities, (6) absence of significant cognitive decline according to selected neuropsychological scales, (7) lack of serious psychiatric conditions, except drug-induced psychosis, (8) absence of on-time major gait problems, (9) good general health, and (10) realistic expectations. Exclusion criteria were (1) patients with previous STN-DBS (2) patients previously treated with APO (previous apomorphine pen injection was permitted), and (3) patients previously treated with levodopa infusion.…”

“…Although several prospective, randomized, and multicenter clinical trials support the use of STN‐DBS, only 1 randomized, double‐blind clinical trial, the TOLEDO study 1 , 2 has been undertaken with APO. 1 , 2 Despite its long‐standing use, many studies that support the use of APO are retrospective and with small sample sizes. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 In terms of motor symptoms, STN‐DBS seems to provide greater clinical improvement than APO, which is generally restricted to infusion during the patient's waking hours and shows a variable effect on dyskinesia.…”

Current Knowledge on the Background, Pathophysiology and Treatment of Levodopa-Induced Dyskinesia—Literature Review

“…The efficacy of CSAI in controlling dyskinesias varies between studies. It is generally considered a likely option in patients with advanced PD [ 182 , 183 , 184 , 185 , 186 ] and has been described as a transitional option between the standard treatment and DBS, providing better control of dyskinesia [ 181 , 187 ]. However, it has sometimes been pointed out, that the increase in LEDD due to combined treatment with oral L-DOPA and CSAI led to a lack of initial improvement in dyskinesias and was a reason for discontinuing therapy [ 181 , 187 , 188 ].…”