Evidence table

Evidence table

Table 4 Ferreira J et al. 2016 (BIPARK I)

Study reference

Ferreira JJ, Lees A, Rocha JF, et al. (2016) Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial The Lancet Neurology 15(2), 154−65

Unique identifier

NCT01568073, EudraCT2010-021860-13

Study type


Aim of the study

To assess the safety and efficacy of opicapone as an adjunct to levodopa compared with placebo or entacapone in people with Parkinson's disease and motor fluctuations

Study dates

Between March 2011 and November 2013


106 specialist centres across 19 European countries (excluding the UK) and Russia

Number of participants

n=600 randomised


Aged 30 to 83 years with Parkinson's disease with end-of-dose motor fluctuations on a stable optimised dose of levodopa and other medicines for Parkinson's disease

Participant's demographics, baseline Parkinson's disease characteristics and treatment history did not differ between the different groups

Inclusion criteria

Clinical diagnosis of Parkinson's disease of at least 3 years' duration; Hoehn and Yahr stage 1 to 3 during on time; at least 1 year of clinical improvement with levodopa treatment; on a stable optimised treatment of 3 to 8 daily doses of levodopa and other Parkinson's disease medicines for at least 4 weeks before screening; signs of end-of-dose motor fluctuations for at least 4 weeks before screening; mean total awake time in the off state of at least 1.5 hours, not including morning akinesia. Participants also had to be able to keep reliable diaries of motor fluctuations

Exclusion criteria

Previous treatment with entacapone; a dyskinesia disability score >3 on item 33 (disability) of the UPDRS; severe or unpredictable periods in the off state, or both; previous surgery or deep brain stimulation for Parkinson's disease; history of neuroleptic malignant syndrome or non-traumatic rhabdomyolysis; concomitant use of tolcapone, apomorphine, entacapone (other than that supplied in the study), neuroleptics, venlafaxine, MAO inhibitors (except selegiline up to 10 mg/day orally or up to 1.25 mg/day buccal and rasagiline up to 1 mg/day) or anti-emetics with antidopaminergic action (except domperidone). Participants with clinically significant unstable cardiovascular disease, psychiatric illness or any other medical condition that increase risks were also excluded


  • Opicapone 5 mg once at night (n=122)

  • Opicapone 25 mg once at night (n=119)

  • Opicapone 50 mg once at night (n=116)


2 comparators:

  • Placebo (n=121)

  • Entacapone 200 mg with each levodopa dose (n=122)

Length of follow-up

14 to 15 weeks.

The participants visited the investigators 7 times:

visit 1, screening; visit 2, randomisation (baseline); visit 3, 1 week after baseline; visit 4, depended on need for levodopa adjustment (between 2 and 3 weeks after baseline); thereafter assessments occurred at 4‑week intervals for visits 5, 6 and 7


Primary outcome:

  • Mean change from baseline to study end in absolute time in the off state, assessed by daily paper participant diaries

Secondary outcomes:

  • Change in the proportion of participants achieving at least 1 hour reduction in absolute time in the off state

  • Change in the proportion of participants achieving at least 1 hour increase in absolute total time in the on state

  • Total time in on state at the end of the study treatment

  • Total time in on state without troublesome dyskinesia

  • Total time in on state with troublesome dyskinesia

  • Percent of time in the off state

  • Percent of time in the on state

  • Percent of time in on state without troublesome dyskinesia

  • Percent of time in on state with troublesome dyskinesia

  • UPDRS total score

  • PDSS score

  • PDQ-39 score

  • NMSS score

  • CGI-C score

  • PGI-C score

Safety outcomes:

  • Percentage of participants with at least 1 TEAE

  • Percentage of participants with TEAE's leading to study medicine discontinuation

  • Number of serious TEAEs

  • Number of serious TEAEs possibly related to treatment

ECG recordings and physical, neurological and dermatological examinations were done at baseline and at the end of the double-blind period (visit 7). Standard laboratory safety tests, the Columbia suicide severity rating scale, and the modified Minnesota impulsive disorder interview were done at baseline and visits 4 to 7

Source of funding


Overall risk of bias/quality assessment

(CASP RCT checklist)

Did the trial address a clearly focused issue?


Was the assignment of patients to treatments randomised?


Were patients, health workers and study personnel blinded?


Were the groups similar at the start of the trial?


Aside from the experimental intervention, were the groups treated equally?


Were all of the patients who entered the trial properly accounted for at its conclusion?


How large was the treatment effect?

See table 5

How precise was the estimate of the treatment effect?

See table 5

Can the results be applied in your context? (or to the local population)


Were all clinically important outcomes considered?


Are the benefits worth the harms and costs?

See key points

Study limitations

  • The study excluded a broad population of participants such as those with severe or unpredictable off episodes or with severe dyskinesia.

  • Study only designed to assess the effect of opicapone in people with end-of-dose wearing off which is characterised by predictability of 'off' episodes.

  • Short study duration of 14 to 15 weeks.

  • Different study populations used to test for the superiority of opicapone versus placebo (full analysis set) and non-inferiority of opicapone versus entacapone (per-protocol set).


a Participants were randomly assigned (1:1:1:1) at baseline using a computer-generated scheme to each study arm using blocks of 8 to 10 depending on regimen stratified by centre. Participants and investigators were masked to treatment throughout the study

b There were 3 main population sets: intention-to-treat analysis (full set) included all randomly assigned participants who took at least 1 dose of study medicine and had at least 1 assessment of time in the off state after baseline; per-protocol set included all participants in the full analysis set who did not majorly deviate from the protocol and; safety set included all participants who received at least 1 dose of study medicine

c There were no UK centres used in the study. The study was conducted in Austria (n=3), Bosnia-Herzegovina (n=16), Bulgaria (n=50), Croatia (n=14), Czech Republic (n=51), France (n=15), Germany (n=35), Hungary (n=10), Italy (n=14), Latvia (n=7), Lithuania (n=15), Poland (n=90), Portugal (n=22), Romania (n=53), Russia (n=34), Serbia (n=36), Slovakia (n=19), Spain (n=37) and Ukraine (n=79)

Opicapone enhances the effects of levodopa so the daily dose of levodopa was reduced (but not frequency) between baseline and up to 3 weeks according to clinical response

Abbreviations: CGI‑C, clinician global impression of change; DDCI, DOPA decarboxylase inhibitor; MAO, monoamine oxidase; NMSS, non-motor symptoms scale; PDQ‑39, 39‑item Parkinson's disease questionnaire; PDSS, Parkinson's disease sleep scale; PGI‑C, patient global impression of change; RCT, randomised controlled trial; SD, standard deviation; UPDRS, unified Parkinson's disease rating scale; TEAE; treatment-emergent adverse event.