For September 2018, we have selected: Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persisten motor fluctuations (TOLEDO): a multicenter, double-blind, randomized, placebo-controlled trial. Lancet Neurol July 25, 2018. doi:10.1016/S1474-4422(18)30284-4.
Subcutaneous infusion of apomorphine, a potent dopamine receptor agonist, is widely used in patients with Parkinson’s disease (PD) with motor fluctuations not optimally controlled with oral medication, but the previous evidence base to support this approach was weak, derived from open label studies.
Our paper of the month reports the first randomized placebo-controlled trial of subcutaneous apomorphine in PD. This phase III “TOLEDO” trial was positive, establishing an evidence base for current clinical practice.
The lead investigators are based in Vienna and patients were recruited from 23 European hospitals. Inclusion criteria were age >30 years, idiopathic PD diagnosed for at least 3 years, based on modified Queen Square Brain Bank criteria, with motor fluctuations not adequately controlled on optimal conventional medical treatment, defined as four or more daily doses of levodopa, and as individually assessed by the investigators. Patients had to fulfill Hoehn and Yahr stage 3 or less when “on”, and 2-5 when “off”. No changes to usual medication were allowed for four weeks prior to study entry, and patient ability to accurately document symptoms in their diaries was assessed. A mean of more than three hours “off’ time/day and no days with fewer than two hours “off” time was required to be eligible for study entry Exclusion criteria included previous surgical treatment for PD, previous use of apomorphine, recent treatment with intrajejunal levodopa, falls due to severe freezing, or significant postural instability during “on” time, mini-mental state examination less than 25/30, recent psychosis of at least moderate severity within the previous year (mild visual hallucinations with preserved insight were allowed), or prolonged QT interval.
Patients were randomly allocated to apomorphine or placebo saline infusion, and initiated as inpatients, for up to 18 hours a day, for 12 weeks. Domperidone was given concurrently as necessary. It was allowed to adjust flow rates during the first four weeks, as well as other oral medications, according to individual patient response, but all study participants and investigators were masked to assigned treatment. No further changes in apomorphine dose were allowed for the remaining eight weeks in the study. Limited rescue doses of levodopa were allowed. The primary outcome measure was the absolute change in “off” time, between baseline and 12 weeks, documented from patient diaries. Secondary outcomes included changes in on-time without troublesome dyskinesia, change in levodopa-equivalent medication dose, UPDRS motor examination scores and the PDQ-8 quality of life measure. Patients with efficacy data for any time-point were included in the analysis. Missing data for the primary endpoint were imputed using a last observation carried forward approach. Wilcoxon rank sum tests were used to compare treatment groups.
Data from 106 patients were analyzed, 53 treated with apomorphine, and 53 with placebo, of whom 71 patients completed the full 12 weeks treatment. Apomorphine at a mean dose of 4.7 mg/hour was found to reduce “off” time by 1.9 hours/day compared with placebo (95% CI -0.6 to -3.2 hours/day, p=0.0025). Common side effects were skin reactions, nausea and somnolence. Six patients in the apomorphine group withdrew due to side effects (one severe hypotension, one leukopenia/anemia, one visual hallucinations, one gait disturbance, one skin reaction, one (unrelated) myocardial infarction. There was no change in UPDRS motor scores or PDQ-8 quality of life measures, but the apomorphine group achieved more “on” time without troublesome dyskinesias and greater reductions in levodopa-equivalent medication doses. The authors concluded that subcutaneous apomorphine provides clinically meaningful benefits in “off” time in PD. A 12 month open-label extension study is now being performed.
“This study represents an important step in establishing optimal treatment regimes for patients with more advanced PD who no longer fully respond to oral treatment”, said Professor Philippe Damier, Department of Neurology, University of Nantes, France. “Whilst a limitation inherent in testing apomorphine is that it is difficult to fully blind participants and assessors, and an imputational statistical approach had to be used because of cohort drop-out rates, overall the rigorous trial methodology provides the best class evidence to date for the benefits of apomorphine, and the positive treatment effect appears meaningful and concordant with clinical experience.”
“This could now pave the way for future trials comparing the different advanced therapies, for example subcutaneous apomorphine and intra-jejunal approaches”, said the leading author of the paper, Pr. Regina Katzenschlager, Department of Neurology, Danube Hospital Vienna, Austria, “and help optimize management for individuals with PD who are no longer responding to oral treatment.”
The other nominees for the September 2018 Paper of the month are:
- Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patients’ data from randomized trials. Lancet Neurol July 12, 2018; doi.org/10.1016/S0140-6736(18)31133-4. In this study, the authors analyzed the effects of different doses of aspirin according to body weight and dose in the long-term primary prevention of cardiovascular events and cancer, stratifying patients by age and sex. As main findings, ≤100 mg aspirin was effective only in patients weighting ≤70 kg, whereas ≥300 mg aspirin were effective only in patients weighting ≥70 Kg. Further research about aspirin dose and bodyweight interaction is clearly needed.
- Ludolph AC, Schuster J, Dorst J, et al., on behalf of the RAS-ALS Study. Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized, double-blind, parallel-group, placebo-controlled, phase 2 trial. Lancet Neurol June 19, 2018; doi.org/10.1016/S1474-4422(18)30176-5. In this German phase II randomized, double-blind, placebo-controlled trial, 1mg rasagiline was studied in 273 patients with possible, probable or definite amyotrophic lateral sclerosis (ALS). At 18 months, no differences between rasagiline and placebo was found related to survival time. Post-hoc analysis suggested that rasagiline could have modifying disease effect in those patients with initial slope of ALS Functional Rating Scale Revised greater than 0.5 per month at baseline.
- Hughes R, Dalakas MC, Merkies I, et al. Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicenter, randomized controlled trial. Lancet Neurol July 9, 2018; doi.org/10.1016/S1474-4422(18)30202-3. The efficacy of 0.5 mg fingolimod in delaying disability progression in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was evaluated in 106 patients from 48 neurology centers worldwide. The trial ended for futility after 44 confirmed worsening events.