Parkinson’s disease with end-of-dose motor fluctuations: opicapone

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

RCT

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

Setting

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

Number of participants

n=600 randomised

Population

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

Intervention(s)

Comparator(s)

2 comparators:

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

Outcomes

Primary outcome:

Secondary outcomes:

Safety outcomes:

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

BIAL

Overall risk of bias/quality assessment

(CASP RCT checklist)

Did the trial address a clearly focused issue?

Yes

Was the assignment of patients to treatments randomised?

Yes

Were patients, health workers and study personnel blinded?

Yes^a

Were the groups similar at the start of the trial?

Yes

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

Yes^b

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

Yes

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)

Unclear^c

Were all clinically important outcomes considered?

Yes

Are the benefits worth the harms and costs?

See key points

Study limitations

Comments

^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.