Product information and disease description Place of product in therapy Approaches to treatment Current treatment options and standard of care

Catechol-O-methyltransferase inhibitors

6 evidence topics · 4 sources

Efficacy conclusions for COMT inhibitors in motor fluctuations

“Opicapone is efficacious to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)
“Three trials evaluated the efficacy of opicapone in reducing OFF‐time compared with placebo.” (opens the source at this quote in a new tab)
“the reduction was around 120 min, with a corresponding increase in ON‐time of ~60 min more than placebo.” (opens the source at this quote in a new tab)
“Entacapone is likely efficacious for the treatment of motor fluctuations in patients with PD in comparison with placebo.” (opens the source at this quote in a new tab)

Opicapone added early in motor fluctuations compared with added levodopa

“After 4 weeks, reductions in daily OFF-time were significantly greater after adding 50 mg opicapone vs adding 100 mg levodopa (− 62 vs − 17 min; mean difference − 45.4. min).” (opens the source at this quote in a new tab)
“The pooled analysis of both ADOPTION trials also showed a significant benefit of adding opicapone with a difference vs adding 100 mg of levodopa of 29 min (p = 0.022)” (opens the source at this quote in a new tab)

Levodopa initiated with entacapone in early disease

“We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4× daily at 3.5-hour intervals.” (opens the source at this quote in a new tab)
“Eligible subjects were men or women aged 30 to 70 years with a diagnosis of PD based on UK brain bank criteria and a disease duration of <5 years from time of diagnosis.” (opens the source at this quote in a new tab)
“Prior exposure to L-dopa for >30 days or within 8 weeks prior to entry, and previous use of a COMT inhibitor, were not permitted.” (opens the source at this quote in a new tab)
“L-dopa/carbidopa in both groups was initiated at a dose of 50/12.5mg twice daily, and titrated to 100/25 (target dose) or 150/37.5mg 4× daily administered at 3.5-hour intervals.” (opens the source at this quote in a new tab)
“With a follow-up time of 134 weeks and an estimated dropout rate of 15%, a sample size of 740 patients provided >80% power to detect a 25% reduction in dyskinesia frequency using the 2-sided log-rank test at an alpha level of 5%.” (opens the source at this quote in a new tab)
“In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02).” (opens the source at this quote in a new tab)
“Kaplan-Meier survival curves show that patients randomized to L-dopa/carbidopa/entacapone (LCE) had greater risk of developing dyskinesia than patients receiving L-dopa/carbidopa (LC) (Cox proportional hazard ratio, 1.29; 95% confidence interval [CI], 1.0–1.65; p = 0.038).” (opens the source at this quote in a new tab)
“Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001).” (opens the source at this quote in a new tab)
“There was a trend to improved UPDRS scores in LCE-treated subjects (difference at final visit, 1.2 points; p = 0.1).” (opens the source at this quote in a new tab)
“Survival time estimates for the first quartile of patients were 90.7 weeks (95% CI, 65.3–104.0) for the LCE group and 117.1 weeks (95% CI, 92.1–132.6) for LC-treated patients.” (opens the source at this quote in a new tab)
“A total of 541 subjects (72.6%) completed their study drug treatment as planned; 265 (71.0%) in the LCE group and 276 (74.2%) in the LC group.” (opens the source at this quote in a new tab)
“LCE showed a trend toward improved UPDRS scores and reduced wearing off compared to LC, consistent with the approved indication of entacapone as an adjunct to L-dopa.” (opens the source at this quote in a new tab)
“The mean L-dopa dose at the end of the titration period was 305.2 and 306.8mg/day in the LCE and LC groups, respectively, and they remained comparable throughout the study.” (opens the source at this quote in a new tab)
“This analysis indicates that LCE-treated patients received significantly more L-dopa dose equivalents than LC patients at the completion of titration, at the time of onset of dyskinesia, and at the final study visit (see Table 5).” (opens the source at this quote in a new tab)
“STRIDE-PD does not support the early administration of L-dopa in combination with entacapone to reduce the risk of motor complications using the dosing regimen employed in this trial.” (opens the source at this quote in a new tab)

Baseline characteristic	Levodopa/carbidopa/entacapone (n = 373)	Levodopa/carbidopa (n = 372)
Age, years, mean ± SD	“60.6±8.7”	“59.8±8.2”
Men, no. (%)	“245 (65.7%)”	“222 (59.7%)”
Caucasian, no. (%)	“352 (94.4%)”	“357 (96.0%)”
Weight, kg, mean ± SD	“79.7±15.8”	“79.1±16.9”
Duration of disease, years, mean ± SD	“2.0±1.6”	“2.0±1.7”
UPDRS total (II + III), mean ± SD	“32.7±12.6”	“31.5±11.9”
UPDRS Part III (motor), mean ± SD	“23.1±9.5”	“22.4±9.0”
Hoehn & Yahr stage, mean ± SD	“1.9±0.5”	“1.9±0.5”
PDQ-39, mean ± SD	“25.2±15.0”	“22.9±13.7”
Previous antiparkinson medication, no. (%)	“263 (70.5%)”	“266 (71.5%)”
Dopamine agonist use, no. (%)	“217 (58.2%)”	“217 (58.3%)”

Evidence-based review conclusions for COMT inhibitors

“The COMT-inhibitors entacapone and opicapone are “clinically useful,” without the safety issue of liver function monitoring required with tolcapone.” (opens the source at this quote in a new tab)
“However, the early use of entacapone in nonfluctuating PD patients resulted in increased motor complications, and thus it remains “not useful.”” (opens the source at this quote in a new tab)
“To date, the new COMT-I opicapone has not been evaluated in nonfluctuating PD patients.” (opens the source at this quote in a new tab)

Levodopa/carbidopa/entacapone compared with levodopa/carbidopa: dyskinesia, wearing off, and dose equivalents

Outcome	Levodopa/carbidopa/entacapone (n = 373)	Levodopa/carbidopa (n = 372)	P value
Dyskinesia frequency at 208 weeks, no. (%)	“144 (38.6)”	“123 (33.1)”	“0.110”
Time to dyskinesia, first-quartile estimate, weeks (95% CI)	“90.7 (65.3–104.0)”	“117.1 (92.1–132.6)”	“0.038”
Disabling dyskinesia, no. (%)	“32 (8.6)”	“23 (6.2)”	“0.201”
Dyskinesia by direct observation, no. (%)	“130 (34.9)”	“110 (29.6)”	“0.118”
Dyskinesia by patient history, no. (%)	“141 (37.8)”	“113 (30.4)”	“0.031”
Dyskinesia by direct observation or patient history on 2 consecutive visits, no. (%)	“120 (32.2)”	“99 (26.6)”	“0.092”
Dyskinesia by direct observation on 2 consecutive visits, no. (%)	“84 (22.5)”	“77 (20.7)”	“0.550”
Dyskinesia frequency at 134 weeks, no.	“128”	“103”	“0.016”
UPDRS II + III, change from baseline to week 130	“8.4”	“7.2”	“0.18”
Wearing off frequency at 208 weeks, no. (%)	“165 (44.2%)”	“189 (50.8%)”	“0.07”
Wearing off frequency at 130 weeks, no. (%)	“139 (45.6%)”	“161 (48.3%)”	“0.53”
Time to wearing off, weeks, mean ± SD	“72.9±50.9”	“78.5±51.5”	“0.53”
Time to wearing off, first-quartile estimate, weeks	“78.0”	“76.0”	“0.6”
Time to wearing off, hazard ratio (95% CI)	“0.94 (0.76–1.17)”	Not applicable	Not reported
Hoehn & Yahr stage, change from baseline	“0.4”	“0.3”	“NS”
Schwab & England score, change from baseline	“−1.4”	“−1.4”	“0.95”
PDQ-39, change from baseline	“2.2”	“2.4”	“0.77”
Levodopa dose equivalents at end of titration	“533.4”	“420.1”	“0.001”
Levodopa dose equivalents at onset of dyskinesia	“659.9”	“535.2”	“0.001”
Levodopa dose equivalents at final study visit	“524.1”	“432.6”	“0.001”

“p values are post hoc, are not corrected, and are for descriptive purposes only.” (opens the source at this quote in a new tab)
“Accordingly, we calculated L-dopa dose equivalents by multiplying the L-dopa dose in LCE patients by 1.3.” (opens the source at this quote in a new tab)
“Wearing off occurred more frequently in LC than LCE patients (50.8% vs 44.2%; p = 0.07), but time to onset of wearing off was similar in the 2 groups.” (opens the source at this quote in a new tab)

Adverse events with levodopa/carbidopa/entacapone compared with levodopa/carbidopa in early disease

Adverse event	Levodopa/carbidopa/entacapone (n = 373), no. (%)	Levodopa/carbidopa (n = 371), no. (%)
Any adverse event	“348 (93.3)”	“336 (90.6)”
Nausea	“114 (30.6)”	“71 (19.1)”
Diarrhea	“66 (17.7)”	“28 (7.5)”
Dizziness	“59 (15.8)”	“46 (12.4)”
Somnolence	“37 (9.9)”	“28 (7.5)”
Vomiting	“22 (5.9)”	“10 (2.7)”
Dyskinesia	“21 (5.6)”	“10 (2.7)”
Orthostatic hypotension	“20 (5.4)”	“13 (3.5)”
Myocardial infarction	“7 (1.9)”	“0 (0.0)”
Prostate cancer	“9 (2.4)”	“2 (0.5)”
Skin cancer	“7 (1.9)”	“12 (3.2)”

“Discontinuations due to adverse events and withdrawal of consent were higher in the LCE group, whereas discontinuation due to unsatisfactory therapeutic effect was higher in the LC group.” (opens the source at this quote in a new tab)
“Surprisingly, LCE was associated with increased myocardial infarction and prostate cancer, whereas LC was associated with increased skin cancer.” (opens the source at this quote in a new tab)
“Impulse control disorders were detected in 14 of 103 (13.6% ) evaluable LCE patients and 15 of 102 (14.7%) evaluable LC patients (see Supplementary Table for further details).” (opens the source at this quote in a new tab)
“Of these, 12 LCE patients (85.7% ) and 10 LC patients (66.7%) were receiving a dopamine agonist.” (opens the source at this quote in a new tab)