Meta-analysis of Placebo-controlled Clinical Trials of Safinamide and Entacapone as Add-on Therapy to Levodopa in the Treatment of Parkinson’s Disease

European Neurological Review, 2015;10(1):15–22 DOI:


Chronic levodopa (L-dopa) treatment of Parkinson’s disease (PD) patients is sooner or later associated with the onset of motor complications, for example wearing off and dyskinesia. PD patients with motor complications usually require the addition of further PD drugs to reduce these L-dopa side effects and enhance its efficacy. Entacapone is an available catechol-O-methyltransferase (COMT) inhibitor, which was extensively investigated as add-on to L-dopa/dopadecarboxylase inhibitor (DDCI) application in PD patients. Safinamide, a water soluble, orally active α-aminoamide derivative, which modulates dopaminergic and glutamatergic neurotransmission with a unique dual mechanism of action, has been studied in two placebo-controlled clinical trials as add-on therapy to L-dopa in fluctuating PD patients. To date, there are no head-to-head clinical trials comparing the efficacy of safinamide and entacapone in the clinic. The aim of this meta-analysis was to determine effect sizes of safinamide and entacapone as add-on treatment to L-dopa in fluctuating PD patients. A systematic search of the literature on entacapone trials up to the end of September 2014 was first conducted on the MEDLINE and EMBASE databases in order to identify appropriate studies. Definition criteria for inclusion were prospective, randomised, placebo controlled and double-blinded trials on the efficacy and safety of entacapone or safinamide in fluctuating L-dopa-treated PD patients. Four studies for entacapone and two trials on safinamide were considered. Data from the safinamide trials were provided by Zambon and therefore ‘safinamide’ was not used as a search term. Safinamide and entacapone treatment was comparable in terms of the main efficacy variables (off time, percentage on time, Unified Parkinson’s Disease Rating Scale). Significant advantages in favour of safinamide were shown in terms of the total incidence of adverse events (AEs) in comparison to placebo, the study discontinuation due to AEs and deaths and in the risk differences of the AEs versus placebo, particularly for nausea, vomiting, diarrhoea, dizziness, urine abnormality and shortness of breath. The odds ratio (OR) of 0.907 for any AE corresponds to an overall AE rate of 68.7 % for safinamide whereas the OR of 2.089 to an overall AE rate of 84.4 % for entacapone.
Keywords: Add-on therapy, entacapone, levodopa, L-dopa, Parkinson’s disease, safinamide
Disclosure: Jörg Schnitker has received funding from Zambon SpA to perform the statistical meta-analysis and to write the report. Thomas Müller participated in advisory boards for the safinamide studies and served as a principal investigator.
Acknowledgments: Editorial assistance was provided by Catherine Amey, PhD, at Touch Medical Media, London, UK.
Received: January 15, 2015 Accepted February 06, 2015
Correspondence: Jörg Schnitker, Institut für angewandte Statistik, Dr. Jörg Schnitker GmbH, Oberntorwall 16-18, D-33602 Bielefeld, Germany. E:
Support: The publication of this article was supported by Zambon SpA. The views and opinions expressed are those of the author and do not necessarily reflect those of Zambon SpA.

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

The signs and symptoms of Parkinson’s disease (PD), a chronic neurodegenerative disorder predominantly characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta, are most effectively treated by levodopa (L-dopa). However, nearly all PD patients experience a fluctuating response to L-dopa sooner or later within the first 5 years of therapy dependent on dosing of L-dopa. End-of-dose wearing off and dykinesias are the most common motor complications associated with L-dopa treatment.1–3 Once they appear, the management of motor complications is often challenging and patients require recurrent drug therapy adjustments to improve fluctuations of movement without exacerbating severe dyskinesia.4

Safinamide recently received a European Committee for Medicinal Products for Human Use (CHMP) positive opinion for the treatment of adult patients with idiopathic PD as add-on therapy to a stable dose of L-dopa, alone or in combination with other PD compounds, in midto- late-stage fluctuating patients. It is a unique molecule with novel mechanisms of action, both dopaminergic and non-dopaminergic ones, which include monoamine oxidase-B (MAO-B) inhibition, sodium channel blockade and calcium channel modulation, thus inhibiting the excessive glutamate release. Safinamide improves motor symptoms, motor complications and quality of life in combination with other PD drugs such as dopamine agonists and L-dopa, reduces off time andextends on time without troublesome dyskinesia.5–7 Entacapone is a potent and specific peripherally acting catechol-O-methyltransferase (COMT) with a nitro-catechol structure.8 It is used as an adjunct to L-dopa/dopadecarboxylase inhibitor (DDCI) therapy and slows the peripheral degradation of L-dopa only (has no anti-parkinsonian activity on its own). There are no head-to-head clinical trials comparing safinamide and entacapone under clinical conditions as an add-on therapy to L-dopa.

The aim of the present analysis is a comparison of entacapone and safinamide as add-on treatments to L-dopa in fluctuating PD patients; therefore, a meta-analysis of all the pertinent double-blind, placebo controlled studies was performed to determine effect sizes of safinamide and entacapone.

Search Strategy
The complete sets of data on placebo-controlled efficacy trials with safinamide as add-on to L-dopa were provided by Zambon, which is currently developing this still investigational compound. These comprise all completed, randomised, double-blind, placebo-controlled studies in PD patients with motor fluctuations, already treated with stable L-dopa dose and who may be receiving further anti-parkinsonian drugs (study 016, NCT01187966, labelled SAF17 and SETTLE, NCT00627640, labelled SAF29,10,11). The duration of the trials was 24 weeks each. A systematic search of the literature up to the end of September2014 was performed on the MEDLINE and EMBASE databases using ‘entacapone’ and ‘levodopa’ or ‘L-dopa’ as search terms. Ongoing trialsand other possible completed trials still unpublished as full papers (available through clinical trial registries, conference proceedings or other literature where it proved difficult to retrieve complete data sets for the analysis) were not identified as part of the search strategy. A 2010 Cochrane Database Systematic Review on add-on therapies to L-dopa treatment was used as a primary reference for the literature.12

Study Selection
Eligible studies for the search were defined as any prospective, randomised, placebo-controlled and double-blinded trials (24 weeks/6 months’ duration) on the efficacy and safety of entacapone in PD patients already receiving L-dopa (usually commercial formulationsof L-dopa in a fixed combination with a DDCI), i.e. L-dopa+carbidopa, L-dopa+benserazide, with motor fluctuations. All other aspects of planned treatment were to be the same in both arms. Therefore, the following types of studies were not considered:

  • Studies in healthy subjects or subjects in early-stage PD, without motor fluctuations;
  • Switch studies (investigating the introduction of entacapone as add-on to L-dopa or L-dopa+DDCI), or any studies with a fixed L-dopa+DDCI+entacapone combination compared with the separate drug formulations, without parallel entacapone placebo treatment groups;
  • Crossover studies – since focus was given to studies of sufficient duration to be comparable to the studies investigating safinamide;
  • Studies not investigating efficacy and safety of entacapone, or entacapone and other treatments (for example, studies regarding physiology parameters, magnetic resonance imaging or pharmacokinetic parameters); and
  • Studies of COMT inhibitors (COMTIs)-genotype interaction, which selected patients based on COMT gene polymorphism.

Study Appraisal and Methods
If different doses and/or dose ranges were found in the selected studies, these were to be analysed both as separate studies and collectively. Among the analysed efficacy parameters were changes from baseline in daily L-dopa dose, total daily off time, total and percent on time and Unified Parkinson’s Disease Rating Scale (UPDRS) scores (part I, II and III only). Safety was analysed mainly on binary criteria (incidence of treatment-emergent adverse events [AEs], AEs plus deaths, discontinuation from the trials and the incidence of some specific AEs). Only parameters that had been evaluated and documented for both treatments were to be included in the analyses.

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Keywords: Add-on therapy, entacapone, levodopa, L-dopa, Parkinson’s disease, safinamide