By Tom Jenkins
For March 2020, we have selected: Olanow et al, Apomorphine sublingual film for off episodes in Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 study. Lancet Neurology; 19: 135-44.
This month’s selected paper addresses a common and practical problem of treating “off” episodes in people with Parkinson’s disease (PD). Apomorphine delivered by subcutaneous pump is already considered for patients with advanced PD, but the present well-conducted study introduces a new sublingual film formulation that appears practically easier and demonstrate efficacy compared to placebo. However, side effects were common and a third of patients in the treatment group discontinued medication. One patient with cardiac risk factors suffered a fatal cardiac arrest during the study. Longer term safety and efficacy are under further investigation.
“Off” episodes are a disabling symptom of PD. Apomorphine is potent a non-ergot dopamine agonist, which is already in clinical use as a subcutaneous formulation for treatment “off” episodes. However, side effects including skin nodules and ulceration can limit practical use in some patients. Apomorphine sublingual film is placed under the tongue and absorbed through the mouth, bypassing first pass metabolism. This phase 3 trial was performed at 32 neurology centres across the USA and Canada. Inclusion criteria were a diagnosis of PD according to UK Brain Bank criteria, responsiveness to levodopa, with at least 2 hours of “off” time, including predictable morning “off” periods and stable doses of anti-Parkinsonian medication. Exclusion criteria included non-idiopathic Parkinsonism, previous surgery for PD, and clinically significant oral pathology, medical, surgical, psychiatric or laboratory abnormalities (in the judgement of the treating clinician). Eligibility was assessed before randomisation by an independent adjudication committee. Usual anti-Parkinsonian medication was continued. Anti-emetics were given prophylactically for 3 days prior to initial dosing and could be either continued or discontinued afterwards, depending on symptoms. There was a 12 week open label run-in phase, during which the dose of apomorphine film was optimised, starting at 10mg and increasing in increments of 5mg to maximum of 35mg, aiming for a full “on” response within 45 minutes without intolerable side effects. Patients were then randomly assigned to either apomorphine film or placebo. Non-stratified randomisation was performed using a web-based interactive system. Patients and investigators were blinded to allocation. Patients were assessed at 4 weekly intervals for 12 weeks with the Unified PD Rating Scale (UPDRS) pre-dose and at 15, 30, 45, 60 and 90 minutes post-dose. The primary outcome was the mean change in the UPDRS from pre-dose to 30 minutes post-dose. There were multiple secondary endpoints which were considered in hierarchical order; the key secondary outcome was considered the percentage of patients at 12 weeks with a self-rated full “on” response within 30 minutes. A mixed effects model for repeated measures statistical model was applied and analysis was by modified intention-to-treat, including all patients who received at least one post-randomisation dose. The funder was responsible for data collection, monitoring and statistical analysis.
Two-hundred and fourteen patients were assessed, 141 entered the open label phase, 54 were randomised to apomorphine and 55 to placebo. No differences were reported between treatment groups. Patients were experiencing a mean of 4 off episodes/day and were on a mean daily dose of 1g of levodopa at study entry. Apomorphine-treated patients scored 7.6 points better on the UPDRS than placebo-treated patients at 12 weeks (95% confidence interval -11.5, -3.7, p=0.0002). Similar benefits were seen at later post-dose times and at the 4 and 8 week visits. Thirty-five percent of patients reported a full “on” response at 30 minutes, compared with 16% of controls (p=0.043).
Fifty-eight percent of patients experienced side effects during the titration phase. Nine percent discontinued treatment at this stage. During the double-blind phase, 89% of patients on apomorphine experienced side effects compared to 45% of placebo patients. In 28%, this resulted in discontinuation of treatment at this stage. More frequent side effects included lip, oropharyngeal, tongue and facial swelling, nausea, somnolescence and dizziness. Three serious events occurred, two in the apomorphine group, a fatal cardiac arrest and an episode of congestive cardiac failure with hypokalaemia in a patient who recovered. Prolonged QT interval occurred in one patient taking apomorphine.
The authors concluded that apomorphine sublingual film is superior to placebo in treatment of “off” periods in PD. They acknowledge that their study population selected for levodopa responders, and longer term safety and efficacy are now being investigated.
“Treatment of “off” periods in patients established on reasonable doses of levodopa is an important area of need in PD and the sublingual route of administration negates some of the drawbacks of subcutaneous apomorphine” said Prof Evzen Ruzicka, General University Hospital, Prague. “The study met its primary and key secondary endpoints of improvement in UPDRS and patient-reported “on” responses, although the high incidence of side effects means it may not be suitable for some patients, and could have affected the blinding. Further longer-term data are required.”