Levodopa/carbidopa/entacapone versus levodopa/dopa-decarboxyiase inhibitor for the treatment of Parkinson’s disease: systematic review, meta-analysis, and economic evaluation

Figures & data

Figure 1 Literature search and study selection.

Abbreviations: DDCI, dopa-decarboxylase inhibitor; LCE, levodopa/carbidopa/entacapone; RCT, randomized controlled trial.

Table 1 Characteristics of included studies

Study	Inclusion criteria	Participants		Intervention		Duration (weeks)	Efficacy outcome		Dropouts
		LCE	Levodopa/DDCI	LCE	Levodopa/DDCI		Primary	Secondary	LCE/levodopa/DDCI
Li et al^Citation21	Mild or moderate PD in (modified) Hoehn–Yahr stage 0–3	n=60 A=53.92±5.39 M/F=36/24	n=52 A=50.10±10.33 M/F=31/21	CR LC 25/100 mg, twice daily, interval ≥6 hours, then titrated gradually (total daily dose ≤600 mg) + entacapone 100 mg	CR LC 25/100 mg, twice daily, interval ≥6 hours, then titrated gradually (total daily dose ≤600 mg)	12	Change from baseline in UPDRS I–VI	NR	NR
Parkinson Study Group^Citation22	Idiopathic PD patients in (modified) Hoehn–Yahr stage 1.5–4; had response to levodopa treatment and motor fluctuations paralleling their levodopa dosing; took a stable regimen of 4–10 daily doses of LC	n=103 A=63.9±8.0 M/F=69/34	n=102 A=62.7±19.7 M/F=64/38	4–10 daily doses of LC + entacapone 200 mg	4–10 daily doses of LC + placebo 200 mg	28	Percentage on time while awake	Percentage on time while awake in the morning, afternoon, and evening; percentage time asleep, total daily levodopa dosage; number of levodopa doses per day and levodopa dose failures; UPDRS total score and mental, motor, and ADL subscale scores; global evaluations	13/10
Fung et al^Citation17	≥30 years old; idiopathic PD with modified Hoehn–Yahr stage 1.0–2.5; 0–3 hours of nondisabling time off over a consecutive 48-hour period; took 3–4 stable equal doses of LC, with total daily levodopa dose of 300–800 mg/day for at least 1 month before study entry	n=93 A=64.8±10.2 M/F=57/36	n=91 A=62.9±9.45 M/F=50/41	3–4 stable doses of LC + entacapone 200 mg	3–4 stable doses of LC	12	Change from baseline to week 12 in total PDQ8 score	Change from baseline to weeks 4 and 12 in UPDRS I, II, III, and IV subscale scores; UPDRS I–III scores combined; number of wearing-off symptoms and proportion of patients experiencing wearing off	10/9
Hauser et al^Citation18	30–80 years old; had impairment warranting treatment with levodopa; UPDRS II + III >18; modified Hoehn–Yahr stage 1.0–2.5	n=208 A=65.3±9.26 M/F=144/64	n=215 A=64.5±8.79 M/F=128/87	LCE 100/25/200 mg, three times daily	LC 100/25 mg, three times daily	39	Change from baseline to week 39 in total UPDRS score (II + III)	Change from baseline in individual UPDRS subscale, PDQ39, PDQ8, modified Hoehn–Yahr stage, and Schwab and England ADL score; CGI score; responder rate	56 (total)
Stocchi et al^Citation19	30–70 years old; required initiation of levodopa therapy; disease duration <5 years; took stable doses of a dopamine agonist or other antiparkinsonian medications (no change in previous 4 weeks), but not amantadine, within preceding 270 days	n=373 A=60.6±8.7 M/F=245/128	n=372 A=59.8±8.2 M/F=222/150	LC 50/12.5 mg twice daily, then titrated to 100/25 or 150/37.5 mg four times daily, at 3.5-hour intervals + entacapone 200 mg	LC 50/12.5 mg twice daily, then titrated to 100/25 or 150/37.5 mg four times daily, at 3.5-hour intervals	134	Time to onset of dyskinesia	Frequency of dyskinesia, change from baseline in total UPDRS (II + III), and time and frequency of wearing-off episodes	108/96
Tolosa et al^Citation20	30–80 years old; received at least 1 month stable doses of IR/SR LC 100/25 mg or SR LC 200/50 mg (total daily levodopa dose 300–600 mg); experienced wearing off and impaired ADLs; had either absent or mild dyskinesia	n=46 A=66.4±8.2 M/F=21/25	n=49 A=66.5±9.0 M/F=27/22	LCE 100/25/200 mg (1 tablet) or LCE 150/37.5/200 mg (1 tablet)	IR LC 100/25 mg (1 tablet) or IR LC 100/25 mg (1.5 tablets)	36	Mean change from baseline to 3-month visit in UPDRS II score	UPDRS I, III, and IV, PDQ39, and QUICK questionnaires	11/10
Lew et al^Citation23	30–80 years old; received at least 1 month stable doses of IR LC; Hoehn–Yahr stage ≤2.5	n=180 A=68.7±9.2 M/F=106/74	n=179 A=68.3±10.4 M/F=108/71	IS group: switched to LCE 12.5/50/200 mg, 25/100/200 mg, or 37.5/150/200 mg immediately	Del group: switched to LCE treatment 4 weeks after completion of the baseline visit to simulate a “placebo” control	4	UPDRS III score	PDQUALIF score, PDQ39 score	44/51

Note: Age presented as mean ± SD.

Abbreviations: A, age; ADL, activity of daily living; DDCI, dopa-decarboxylase inhibitor; Del, delayed switch; IS, immediate switch; M, male; F, female; IR, immediate release; LCE, levodopa/carbidopa/entacapone; NR, not reported; PD, Parkinson’s disease; SR, slow release; PDQ, Parkinson’s Disease Questionnaire; PDQualif, PD quality-of-life instrument; UPDRS, Unified Parkinson’s Disease Rating Scale.

Table 2 Risk of bias of randomized controlled trials

Study	Random-sequence generation	Allocation concealment	Blinding	Incomplete outcome data	Selective reporting	Other source of bias
Li et al^Citation21	Unclear	Unclear	Unclear	Low	Unclear	Low
Parkinson Study Group^Citation22	Low	Low	Low	Low	Low	Low
Fung et al^Citation17	Low	Low	Low	Low	Low	Low
Hauser et al^Citation18	Low	Low	Low	Low	Low	Low
Stocchi et al^Citation19	Low	Low	Low	Low	Low	Low
Tolosa et al^Citation20	Low	Low	Low	Low	Low	Unclear
Lew et al^Citation23	Low	High	High	Low	Unclear	Unclear

Figure 2 Changes in UPDRS scores from baseline.

Abbreviations: UPDRS, Unified Parkinson’s Disease Rating Scale; DDCI, dopa-decarboxylase inhibitor; LCE, levodopa/carbidopa/entacapone.

Figure 3 Risk of serious AEs, discontinuation due to AEs, and total AEs.

Abbreviations: AEs, adverse events; LCE, levodopa/carbidopa/entacapone; DDCI, dopa-decarboxylase inhibitor.

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