A literature search was conducted which identified 7 references (see the search strategy for full details). These references were screened using their titles and abstracts and 1 reference was obtained and assessed for relevance.
From the search, 1 randomised controlled trial (RCT; Ferreira et al. 2016; BIPARK I) was identified and included in the evidence summary. A summary of the included study is shown in table 2 (see the evidence table for full details).
An additional 14‑ to 15‑week RCT (Lees et al. 2016; BIPARK II) that was considered by the European Medicines Agency during the regulatory process was published after the search was conducted. The results of this study are briefly summarised in the review of the clinical effectiveness.
Table 2 Summary of the included study
Intervention and comparison
Ferreira et al. 2016 (BIPARK I)
Aged 30 to 83 years with PD and end-of-dose motor fluctuations
Opicapone 5 mg, 25 mg and 50 mg vs placebo or entacapone 200 mg (taken with each levodopa intake)
Mean change in absolute off time from baseline to study end
Abbreviations: PD, Parkinson's disease; RCT, randomised controlled trial.
This evidence summary is based on a 14‑ to 15‑week, double-blind, placebo- and active-controlled RCT of opicapone as an adjunct to levodopa in people with Parkinson's disease experiencing end-of-dose motor fluctuations (Ferreira J et al. 2016; BIPARK I). All participants had a clinical diagnosis of Parkinson's disease for 3 or more years and were taking a stable dose of levodopa (immediate- and controlled-release). Many participants were also taking other Parkinson's disease medicines, most commonly a dopamine agonist.
The BIPARK I study evaluated the superiority of opicapone to placebo and also the non-inferiority of opicapone to entacapone 200 mg. There were 5 treatment arms in the study. See table 2 for details.
This evidence summary will mainly focus on reporting the results of the licensed opicapone 50 mg formulation.
The primary outcome was the change from baseline to study end in the absolute time in the off state as assessed by using daily participant diaries. Analysis of the outcome used a hierarchical procedure for each opicapone dose, with superiority over placebo being established before determining non-inferiority to entacapone.
At 14 to 15 weeks the mean change from baseline in absolute time in the off state to study end was largest in the opicapone 50 mg group (−116.8 minutes), followed by entacapone (−96.3 minutes) and the placebo group (−56.0 minutes) in the intention to treat [ITT] analysis. The mean difference in change from baseline between opicapone 50 mg and placebo was −60.8 minutes (95% confidence interval [CI] −97.2 to −24.2, p=0.0015) demonstrating superiority to placebo (Ferreira et al. 2016). Superiority to placebo was not shown by opicapone 5 mg and 25 mg. There was a statistically significant reduction in the absolute mean off time when entacapone was compared with placebo of −40.3 minutes (95% CI −76.2 to −4.2, p=0.014). Ferreira et al. (2016) reported that similar results were seen in the per-protocol analysis (data not shown by the authors).
In the non-inferiority analysis, the mean difference in the absolute time in the off state with opicapone 50 mg compared with entacapone was −26.2 minutes (95% CI −63.8 to 11.4, p=0.0051 [per-protocol analysis]). Based on the predefined non-inferiority margin of 30 minutes, opicapone 50 mg was found to be non-inferior to entacapone.
Responder rates for the off and on state (percentage of participants achieving a 1 hour or more reduction in absolute time in the off state or 1 hour or more increase in the absolute time in the on state) were reported by the authors as key secondary outcomes. There was a statistically significant higher responder rate for the off and on state in the opicapone 50 mg group when compared with placebo (70% versus 48%, odds ratio [OR] 2.5, 95% CI 1.5 to 4.3; p=0.001 and 65% versus 58%, OR 2.2, 95% CI 1.3 to 3.8; p=0.003). No statistically significant difference was found for entacapone when compared with placebo or with opicapone 50 mg for these outcomes (p>0.05).
The least squares mean difference in the total time in the on state at the end of the study when compared with placebo was found to be the greatest with opicapone 50 mg at 71.9 minutes (95% CI 35.0 to 108, p=0.0001), followed by entacapone at 52.6 minutes (95% CI 16.1 to 89.1, p=0.005). There was no statistically significant difference when opicapone 50 mg was compared with entacapone for this outcome (p=0.30).
There was a statistically significant improvement in on time without troublesome dyskinesia by approximately 60 minutes with opicapone 50 mg when compared with placebo (95% CI 23.8 to 101.4, p=0.002). A statistically significant improvement was also seen for this outcome with entacapone when compared with placebo (47.6 minutes, 95% CI 9.3 to 6.0, p=0.02). There was no statistically significant difference when opicapone 50 mg was compared with entacapone for this outcome (p=0.45).
The percentage of participants with any improvement from baseline in clinician global impression of change (CGI‑C) and the patient global impression of change (PGI‑C) was higher with opicapone groups compared with placebo and entacapone groups. A statistically significant difference was found in CGI‑C with opicapone 50 mg when compared with placebo (73% versus 49.9%, p=0.0005). No statistically significant difference was found in CGI‑C with entacapone when compared with placebo (50.9%, p=0.61). There was a statistically significant improvement in PGI‑C with opicapone 50 mg when compared with placebo (72.1% versus 50.9%, p=0.0008). No statistically significant improvement was found with entacapone when compared with placebo (52.5%, p=0.47). Compared with entacapone, there was a statistically significant improvement in CGI‑C and PGI‑C with opicapone 50 mg (p=0.007 and p=0.0091 respectively).
There was an improvement in health-related quality of life, motor scores and daily activities scores (assessed using UPDRS, PDSS, PDQ-39 and NMSS) from baseline to end point in all treatment groups (including placebo). The differences between active treatment (opicapone 50 mg and entacapone) and placebo groups were not statistically significant.
There was a decrease in the mean daily dose of levodopa therapy from baseline to end point in all treatment groups. This was the greatest for opicapone 50 mg (−31.6 mg) when compared with placebo (−6.1 mg), however statistical significance was not reported. Entacapone reduced the mean daily levodopa dose by 14.5 mg.
An overview of the results for clinical effectiveness can be found in the results tables.
An additional multicentre (including the UK) 14‑ to 15‑week RCT (Lees et al. 2016) [BIPARK II]) (n=427) study found that there was a statistically significant reduction in the time in off state by 54.3 minutes (95% CI −96.2 to −12.4, p=0.008) with opicapone 50 mg when compared with placebo. The study also reported findings from a 1‑year open-label phase during which all participants received active treatment with opicapone (n=367). The participants started open-label treatment with 25 mg opicapone, which could be titrated up to 50 mg if greater symptom control was needed (Lees et al. 2016). The mean change in off time from the start to the end of the open-label phase was −18.31 minutes (95% CI −43.56 to +6.95) suggesting that the reduction in off time was sustained for 1 year.
The SPC states that opicapone is contraindicated in people with phaeochromocytoma, paraganglioma or other catecholamine secreting neoplasms. Opicapone is also contraindicated in people with a history of neuroleptic malignant syndrome and/or non-traumatic rhabdomyolysis.
Concomitant use with monoamine oxidase inhibitors (for example phenelzine, tranylcypromine and moclobemide) other than those for the treatment of Parkinson's disease is also contraindicated (SPC: opicapone). The SPC states that concomitant use with tricyclic antidepressants and noradrenaline re‑uptake inhibitors should be considered with appropriate caution and co‑administration with medicines metabolised by CYP2C8 such as repaglinide must be avoided. The SPC also states that concomitant use with safinamide should be considered with appropriate caution as there is no experience when used together.
The SPC states that it is often necessary to adjust the daily dose of levodopa within the first days to first weeks after starting treatment with opicapone to reduce levodopa-related dopaminergic adverse reactions such as dyskinesia.
In the BIPARK I study, safety outcomes were analysed for all participants who received at least 1 dose of the study medicine (n=599). The number of participants with treatment-emergent adverse events leading to discontinuation of opicapone 50 mg was 5 (4%), compared with 8 in the placebo group (7%) and 8 in the entacapone group (7%). Diarrhoea, (2 in the entacapone group and 1 in the placebo group), visual hallucinations (1 in the opicapone 5 mg group, 2 in the opicapone 25 mg group, and 2 in the opicapone 50 mg group) and dyskinesia (2 in the opicapone 5 mg group) were common adverse events leading to treatment being discontinued. The number of participants experiencing at least 1 treatment-emergent adverse event was similar for all doses of opicapone and placebo (between 60 and 62 participants). The number of participants with serious treatment-emergent adverse events was the greatest for entacapone (n=8), followed by placebo (n=6) and opicapone 50 mg (n=4), statistical analysis was not reported.
Impulse control disorders can occur in people treated with dopamine agonists and/or other dopaminergic treatments. The SPC advocates regular monitoring for the development of impulse control disorders and review of treatment if symptoms develop. People taking dopaminergic treatments and their carers should be made aware of the behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating (SPC: opicapone).
In the BIPARK I study, impulse control disorders related to treatment were reported in 10 participants or fewer per group; opicapone 50 mg (n=8), entacapone (n=10) and placebo (n=5). The most commonly reported disorder in all groups was buying disorder (Ferreira et al. 2016).
The SPC for opicapone reports that dyskinesia is a very common adverse reaction occurring in 10/100 people or more. Common adverse reactions, occurring in 1/100 people or more, are dizziness, headache, somnolence, orthostatic hypotension, constipation, dry mouth, vomiting and muscle spasms.
In the BIPARK I study, dyskinesia was the most common reported treatment-emergent adverse event across treatment groups. This was most commonly reported with opicapone 50 mg (16%; n=18), when compared with entacapone (8%; n=10) and placebo (4%; n=5). Other adverse events affecting 5% or more participants taking opicapone included dizziness, insomnia and hallucinations (statistical analysis not reported). There was no increased suicidality in the opicapone or entacapone groups compared with placebo (Ferreira et al. 2016).
The European public assessment report (EPAR) includes results from the pooled analysis of BIPARK I and BIPARK II studies and states that the incidence of treatment-emergent serious adverse events was similar across the total opicapone (3.5%) and placebo (4.3%) groups (statistical analysis not reported).
An overview of the results for safety and tolerability can be found in the results tables.
For full information see the SPC for opicapone.
The RCT (BIPARK I) investigating the safety and efficacy of opicapone was a double-blind, placebo- and active-controlled study, which included a total of 600 participants across 106 centres in 19 European countries and Russia (Ferreira et al. 2016). The primary efficacy outcome measure was the reduced time in off state, which the EPAR for opicapone states is a valid and clinically relevant measure of efficacy.
The number of participants who withdrew from the treatment groups due to adverse events or for safety or ethical reasons were: placebo (n=9); entacapone (n=9); opicapone 5 mg (n=8); opicapone 25 mg (n=8); and opicapone 50 mg (n=6). The baseline participant clinical characteristics, demographics and treatment history were similar between the treatment groups. The active-control group received entacapone 200 mg with each levodopa dose. Entacapone is the most commonly used catechol-O-methyl transferase (COMT) inhibitor in practice for end-of-dose motor fluctuations and so was an appropriate comparator in the opicapone study. Masking of the opicapone and placebo was carefully maintained in the study and also the differences in frequency of administration of entacapone (up to 8 times each day) and opicapone (once daily) was taken into account as participants in the opicapone groups took placebo during the day with levodopa doses and active treatment as the bedtime dose (Ferreira et al. 2016).
Ferreira et al. (2016) used different study populations to test for superiority versus placebo (ITT analysis) and non-inferiority versus entacapone (per-protocol analysis). Both analyses support the efficacy of opicapone 50 mg compared with placebo and non-inferiority of opicapone 50 mg to entacapone. Based on the authors assuming a mean reduced off time from baseline to study end of 75 minutes for entacapone, a non-inferiority margin of 30 minutes was used to test for non-inferiority. Specialists involved in the production of this evidence summary commented that a non-inferiority margin of 30 minutes was appropriate to test for non-inferiority of opicapone with entacapone. The results of the primary outcome analysis were similar in the sensitivity analysis that was carried out. A mixed model was used for repeated measurements to take into account the study using a last observation carried forward method to adjust for missing data from the participant's diaries (Ferreira et al. 2016).
The EPAR for opicapone includes subgroup analysis on the primary efficacy outcome. It states that none of the subgroup analysis showed an interaction with the subgroup tested, indicating that results showing superiority of opicapone compared with placebo and non-inferiority to entacapone were consistent across all subgroups evaluated. Subgroup analysis included age, gender, modified Hoehn and Yahr staging (UPDRS V) at baseline, levodopa formulation and daily dose, use of dopamine agonists and/or monoamine oxidase (MAO) inhibitors at baseline and different geographical areas.
Dose adjustments of levodopa were allowed between baseline and up to 3 weeks according to clinical response in the BIPARK I study, but the baseline dose was not to be exceeded and adjustments were not allowed after the first 3 weeks. This does not reflect routine practice, as the dose of levodopa can be adjusted when adjunctive therapy is started.
The BIPARK I study was carried out over a short period of up to 15 weeks and excluded a broad population of people with Parkinson's disease. Opicapone was investigated in mainly white people (mean age of approximately 64 years) with Parkinson's disease taking a stable optimised regimen of 3 to 8 daily doses of levodopa and other medicines for Parkinson's disease. People who had previously taken entacapone, had severe dyskinesia and/or severe or unpredictable periods in the off state, or both were excluded from the study. Some of the participants in the BIPARK I study were taking anticholinergics (5%) and medicines for Parkinson's disease that are not available in the UK. In the NICE guideline on Parkinson's disease, anticholinergics are not included as an option for adjuvant therapy in people with later Parkinson's disease. Furthermore, the BIPARK I study was carried out in Europe (excluding the UK) and Russia, and participants may not reflect UK population and routine clinical practice.
An overview of the quality assessment of the included study can be found in the evidence table.