Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial

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Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial Robert A Hauser, Ann Hsu, Sherron Kell, Alberto J Espay, Kapil Sethi, Mark Stacy, William Ondo, Martin O’Connell, Suneel Gupta, for the IPX066 ADVANCE-PD investigators*

Summary Lancet Neurol 2013; 12: 346–56 Published Online February 26, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70025-5 See Comment page 325 *Investigators listed in the appendix University of South Florida, Tampa, FL, USA (R A Hauser MD); Impax Laboratories, Hayward, CA, USA (A Hsu PhD, S Kell MD, M O’Connell PhD, S Gupta PhD); University of Cincinnati Academic Health Center, Cincinnati, OH, USA (A J Espay MD); Georgia Health Sciences University, Augusta, GA, USA (K Sethi MD); Duke University School of Medicine, Durham, NC, USA (M Stacy MD); and The University of Texas Health Science Center at Houston, Houston, TX, USA (W Ondo MD) Correspondence to: Dr Robert A Hauser, University of South Florida, Parkinson’s Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, 4001 East Fletcher Avenue, 6th Floor, Tampa, FL 33613, USA [email protected]

See Online for appendix

Background IPX066 is an oral, extended-release, capsule formulation of carbidopa-levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations. Methods We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson’s disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov, number NCT00974974. Findings Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-levodopa (mean 3·6 doses per day [SD 0·7]) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-levodopa (mean 5·0 doses per day [1·2]). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-levodopa and 29·79% (15·81) for immediate-release carbidopa-levodopa (mean difference –5·97, 95% CI –9·05 to –2·89; p<0·0001). Extended-release carbidopa-levodopa reduced daily off-time by, on average, an extra –1·17 h (95% CI –1·69 to –0·66; p<0·0001) compared with immediate-release carbidopalevodopa. During dose conversion with extended-release carbidopa-levodopa, 23 (5%) of 450 patients withdrew because of adverse events and 13 (3%) withdrew because of a lack of efficacy. In the maintenance period, the most common adverse events were insomnia (seven [3%] of 201 patients allocated extended-release carbidopa-levodopa vs two [1%] of 192 patients allocated immediate-release carbidopa-levodopa), nausea (six [3%] vs three [2%]), and falls (six [3%] vs four [2%]). Interpretation Extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson’s disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency. Funding Impax Laboratories.

Introduction Motor fluctuations are common in advanced Parkinson’s disease despite the availability of oral levodopa formulations and various other drugs for this disease.1 Several studies have shown that wearing-off and off-time have a strongly negative effect on quality of life.2–5 Therefore, an easily administered and highly effective Parkinson’s disease drug is needed that provides sustained benefit throughout the day. Although a controlled-release formulation of carbidopa-levodopa is available, patients with moderate-to-severe motor fluctuations given this formulation in clinical trials did not consistently have 346

significant reductions in off-time or increases in ontime compared with patients given immediate-release carbidopa-levodopa.6–10 Potential shortcomings of the controlled-release formulation include increased time to onset of effect, increased dyskinesia, and a lessened predictability of response11–15 compared with immediaterelease carbidopa-levodopa. Nonetheless, in clinical trials,6,16 global assessments of improvement by patients and physicians were better for controlled-release than for immediate-release carbidopa-levodopa. IPX066 (Rytary; Impax Laboratories, Hayward, CA, USA) is an oral, extended-release capsule that contains www.thelancet.com/neurology Vol 12 April 2013

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beads of carbidopa and levodopa that dissolve at various rates in the gastrointestinal tract. It produces rapid attainment and maintenance of therapeutic levodopa plasma concentrations, often allowing dosing intervals of approximately 6 h.17 In 27 patients with advanced Parkinson’s disease, extended-release carbidopa-levodopa produced plasma levodopa profiles showing an onset of effect similar to that of immediate-release carbidopalevodopa, and a longer duration of benefit after one dose.17 We aimed to assess efficacy and safety of extended-release carbidopa-levodopa compared with immediate-release carbidopa-levodopa as an active comparator in patients with advanced Parkinson’s disease and motor fluctuations.

Methods Study design and participants We undertook a phase 3, randomised, double-blind, double-dummy, active-control, parallel-group trial at 68 academic and clinical centres in North America and Europe. Key inclusion criteria were a diagnosis of Parkinson’s disease according to UK Parkinson’s disease Brain Bank Criteria, age 30 years or older at time of diagnosis, Hoehn and Yahr stage I–IV in the on-state, a mini-mental state exam score of 26 or more, treatment with a stable regimen of an immediate-release levodopa formulation for at least the 4 weeks before screening, a total daily levodopa dose of at least 400 mg and a daily dosing frequency of at least four times per day, and a 3-day average of at least 2·5 h off-time per day on Parkinson’s disease diaries18 at baseline (ie, before any dose adjustment was made) and at visit 2 (after dose adjustment was done). Concomitant therapy with dopamine agonists, monoamine oxidase-B inhibitors, amantadine, and anticholinergic drugs at stable doses was permitted. Key exclusion criteria were atypical or secondary parkinsonism, lack of response to levodopa, previous neurosurgical treatment for Parkinson’s disease, severe dyskinesia, active psychosis or treatment with antipsychotic drugs, or previous participation in an extended-release carbidopa-levodopa study. Participants with impulse control disorders, assessed with the modified Minnesota impulsive disorders interview (m-MIDI),19,20 were excluded from study entry at screening and from double-blind treatment at randomisation. We assessed four impulse control disorders: gambling, sexual behaviour, buying disorder, and binge eating. The study was done according to good clinical practice guidelines and was approved by appropriate institutional review boards. Before enrolment, all patients provided written informed consent.

Procedures Patients initially underwent a 3-week, open-label, dose-adjustment period (weeks 1–3), during which investigators adjusted the dose and frequency of immediate-release carbidopa-levodopa as necessary to www.thelancet.com/neurology Vol 12 April 2013

achieve optimum motor function. The dose-adjustment period was followed by a 6-week, open-label, extendedrelease carbidopa-levodopa dose-conversion period (weeks 4–9). A conversion table was provided for initial conversion to this drug formulation (appendix). The initial conversion was done on the basis of the total daily dose of the immediate-release formulation achieved at the end of week 3. The recommended initial extendedrelease carbidopa-levodopa dose regimens were expected to provide, on average, about 10% greater levodopa area under the time-concentration curve (AUC) than with immediate-release carbidopa-levodopa on the basis of a previous study.17 The recommended initial extendedrelease carbidopa-levodopa dosing frequency was three times a day during waking hours at 6 h intervals. Doses and dosing frequency were then adjusted so that, by the end of week 9, patients were to be maintained on a stable regimen with a single strength of capsule. Each dose could consist of one or more such capsules, but the dosing frequency could not be more than five times per day (including, if needed, a bedtime dose). Patients were then randomly allocated to 13 weeks of double-blind treatment (weeks 10–22) with the immediate-release regimen achieved at the end of week 3 plus placebo for the extended-release carbidopa-levodopa regimen achieved at the end of week 9, or the extended-release carbidopa-levodopa regimen achieved at the end of week 9 plus placebo for the immediate-release regimen achieved at the end of week 3. Impax Laboratories manufactured IPX066 (1:4 ratio of carbidopa:levodopa) in extended-release capsules with dose strengths as follows: 95 mg (23·75 mg carbidopa and 95 mg levodopa); 145 mg (36·25 mg and 145 mg); 195 mg (48·75 mg and 195 mg); and 245 mg (61·25 mg and 245 mg). Immediate-release carbidopa-levodopa (Sinemet 25/100 mg) was obtained from Merck (Whitehouse, NJ, USA). Impax Laboratories manufactured matching placebos.

Randomisation and masking Patients entering the double-blind study period were randomly allocated (1:1) to active treatment with extended-release carbidopa-levodopa or immediate-release carbidopa-levodopa plus placebo matching the other study drug. Treatment was assigned by study-site contact with an interactive web-response system that held the masked assignment codes. Patients, sponsor personnel, and site personnel were masked to treatment assignment.

Outcomes For assessment of efficacy, patients completed Parkinson’s disease diaries18 for 3 days before study visits at baseline, 3 weeks (end of dose-adjustment period), 9 weeks (end of conversion period), 12 weeks and 17 weeks (3 weeks and 8 weeks after randomisation), and end of study (22 weeks or earlier if patients had early termination of study drug). We scored patients with the 347

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unified Parkinson’s disease rating scale (UPDRS)21 at screening, baseline, at weeks 3, 9, 12, 17, and at end of study. We obtained patient global impression of change (PGI-C) and clinician global impression of change (CGI-C) scores at end of study. We also calculated the proportion of patients with at least 1 h improvement in off-time from baseline (responder analysis). Additional quality-of-life and functional assessments were undertaken at baseline, randomisation, and end of study: the 39-item Parkinson’s disease questionnaire (PDQ-39),22 the short form-36 health survey (SF-36),23 the modified

Rankin scale (mRS),24 the EuroQol 5-dimension qualityof-life scale (EQ-5D),25 and the scales for outcomes in Parkinson’s disease–sleep scale (SCOPA-S).26 We recorded treatment-emergent adverse events throughout the study. We assessed vital signs, including blood pressure, heart rate, temperature, and respiratory rate (after patients were supine for 5 min), and blood pressure and heart rate (after patients were standing for 2 min) at screening, baseline, and weeks 3, 5, 7, 9, 12, 17, and 22. We did electrocardiograms at screening and week 22. We did an m-MIDI at screening and weeks 9, 12, and

567 patients screened

96 screening failures 42 did not meet inclusion criteria 54 met exclusion criteria

471 enrolled

21 discontinued from carbidopa-levodopa dose adjustment 3 adverse events 1 protocol violation 1 non-compliance 7 withdrawal by patient 9 other reasons*

450 completed open-label dose adjustment

57 discontinued from IPX066 dose conversion 23 adverse events 2 died 4 protocol violations 13 lack of efficacy 12 withdrawal by patient 3 other reasons*

393 completed open-label IPX066 dose conversion

201 randomly allocated IPX066 double-blind maintenance

186 completed study

201 analysed

15 discontinued from IPX066 treatment group 3 adverse events 1 protocol violation 2 lack of efficacy 5 withdrawal by patient 4 other reasons*

192 randomly allocated immediate-release carbidopa-levodopa double-blind maintenance

182 completed study

10 discontinued from immediate-release carbidopa-levodopa group 3 adverse events 1 protocol violation 1 non-compliance 2 lack of efficacy 1 lost to follow-up 2 withdrawal by patient

192 analysed

Figure 1: Trial profile IPX066 is an oral formulation of extended-release carbidopa-levodopa. *Investigator-adjudicated; most reasons were inclusion or exclusion criteria violations (12 patients) but also included decisions by the patient (one patient), a site principal investigator (one patient), or the sponsor’s medical officer (two patients) to withdraw the patient from the study.

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22. We collected blood samples for laboratory safety tests at screening and weeks 9 and 22. Because fixed-dose carbidopa-levodopa combinations at a 1:4 ratio have been in clinical use since 1975 and their safety profile is well established, an independent safety-data monitoring board was not constituted. However, designated personnel including the sponsor’s medical monitors reviewed masked safety data in real-time via electronic data capture.

Statistical analysis We estimated the sample size on the basis of a study showing a mean difference of 0·9 h in off-time between immediate-release carbidopa-levodopa and this treatment plus entacapone.27 With the assumption of a mean difference between treatments of 0·9 h (SD 3 h) in the reduction in off-time, about 175 randomised patients per group would be required to provide around 80% power. Therefore, we planned to enrol 420 patients to allow us to randomly allocate at least 350 after accounting for loss to follow-up. For efficacy analyses, we included all randomly allocated patients analysed on an intention-to-treat basis. Data from patients who withdrew after randomisation but before completion of 13 weeks of double-blind treatment were included with a last observation carried forward approach if they had at least one efficacy measure after randomisation. If patients had no such measure, they were assigned the average of values from all randomised patients at end of study, irrespective of treatment. The primary efficacy measure was off-time as a percentage of waking hours, as assessed from Parkinson’s disease diary data. We analysed the primary measure at end of study adjusted for baseline with a two-factor maineffects ANCOVA model with treatment and centres as factors and percentage off-time during waking hours at baseline (study entry) as a covariate. To further describe differences in off-time, we examined change in off-hours from baseline to end of study along with ANCOVA analyses of end-of-study off-hours. Other efficacy analyses included on-time without troublesome dyskinesia, on-time with troublesome dyskinesia, PGI-C and CGI-C ratings, UPDRS on-state parts I, II, III, IV, II and III, and I, II and III scores, UPDRS off-state part II scores, PDQ-39 scores, SF-36 scores, mRS scores, SCOPA-S scores, and ED-5D scores. For continuous secondary endpoint variables, we did similar analyses to those for the primary endpoint (ie, ANCOVA and baseline values as the covariate). We examined categorical variables with Cochran-MantelHaenzel techniques. We addressed the issue of multiple comparisons by analysing efficacy in a hierarchical manner. We tested the primary efficacy variable of off-time as a percentage of waking hours first. If this result was significant (p<0·05), off-time in hours was tested next, followed by on-hours without troublesome dyskinesia. We then tested PGI-C and CGI-C, followed by UPDRS II and III. If these outcomes were significant, we analysed the other measures non-hierarchically. Significance levels www.thelancet.com/neurology Vol 12 April 2013

(p values) were based on the preplanned ANCOVA model described previously. We also calculated 95% CIs for the end-of-study sample mean differences, which are unbiased estimators that were not used for significance testing. Calculation and description of the mean dosing frequency of double-blind extended-release carbidopalevodopa and immediate-release carbidopa-levodopa was preplanned. As post-hoc analyses, we assessed the mean dosing frequency of double-blind extended-release carbidopa-levodopa versus immediate-release carbidopalevodopa and the number of capsules or tablets administered daily with unpaired t tests. This study is registered with CinicalTrials.gov, number NCT00974974.

Role of the funding source The study was funded and conducted by Impax Laboratories. Data collection was coordinated by the sponsor and designates, who also conducted the study. Impax also supported reporting of study results as employer of some of the authors and by providing funding for editorial support. All authors had full access to all data and contributed to manuscript revision. The corresponding author wrote the first draft and had the final responsibility for the decision to submit the paper for publication.

Results Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 patients (figure 1). 393 patients completed open-label conversion and were randomly allocated in the doubleblind maintenance period, and 368 completed the 22 week study (the last on Jan 19, 2011). Table 1 shows All enrolled (n=471)

Randomly allocated (n=393)

Extended-release Immediaterelease carbidopacarbidopalevodopa (n=201) levodopa (n=192)

Age, years

63·5 (9·5)

63·2 (9·4)

Sex, male

292 (62%)

254 (65%)

129 (64%)

63·1 (10·0)

125 (65%)

63·4 (8·8)

Ethnic group, white

456 (97%)

382 (97%)

196 (98%)

186 (97%)

Weight, kg

79·8 (16·2)

80·8 (16·2)

80·0 (15·9)

81·5 (16·5)

Age at PD diagnosis, years

55·8 (10·3)

55·8 (10·2)

55·5 (10·9)

56·1 (9·4)

PD duration, years Mini-mental state exam score

7·7 (4·9) 29·0 (11·1)

7·4 (4·5)

7·5 (4·8)

7·3 (4·2)

29·0 (1·1)

29·1 (1·0)

29·0 (1·1)

Hoehn and Yahr stage I

13 (3%)

11 (3%)

4 (2%)

7 (4%)

II

247 (52%)

213 (54%)

110 (55%)

103 (54%)

III

189 (40%)

152 (39%)

77 (38%)

75 (39%)

IV

22 (5%)

17 (4%)

10 (5%)

V UPDRS (parts I, II, and III)* Daily off-time, h

0 33·9 (15·5) 5·98 (2·12)

0 34·2 (15·3) 5·97 (2·12)

0 34·1 (14·9) 6·05 (2·26)

7 (4%) 0 34·3 (15·8) 5·89 (1·97)

Data are mean (SD) or n (%). PD=Parkinson’s disease. UPDRS=unified Parkinson’s disease rating scale. *UPDRS parts II and III in the on-state.

Table 1: Demographics and baseline characteristics

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baseline characteristics of the study population. Randomly allocated patients had a mean age of 63·2 years (SD 9·4), Parkinson’s disease duration of 7·4 years (4·5), and a mean daily off-time of 5·97 h (2·12) at study entry. Concomitant drug use was much the same between treatment groups and showed little change throughout the study phases (appendix). Off-time (percentage of waking day and hours) was reduced by a greater amount for patients treated with extended-release carbidopa-levodopa than it was for those treated with immediate-release carbidopalevodopa (table 2). Extended-release carbidopa-levodopa was associated with a 1·17 h greater reduction in daily off-time (95% CI –1·69 to –0·66; p<0·0001). From baseline to end of study, more patients in the extendedrelease group than in the immediate-release group had at least a 1 h reduction in daily off-time (table 2). Figure 2 shows the mean daily off-times for randomly allocated patients throughout the study, which differed at all timepoints after randomisation. Mean on-time without troublesome dyskinesia was increased in the extendedrelease carbidopa-levodopa group compared with the immediate-release carbidopa-levodopa group (table 2), but mean increases in on-time with troublesome dyskinesia did not differ between groups. Mean UPDRS parts II and III scores were improved by a greater amount in the extended-release carbidopa-

levodopa group than in the immediate-release carbidopalevodopa group, as were changes in all other UPDRS categories apart from part IV scores (table 2). In addition, mean PGI-C and CGI-C ratings favoured extended-release carbidopa-levodopa (table 2). Mean changes in PDQ-39 total score and in the mobility subscore (but not other subscores) favoured extended-release carbidopa-levodopa (table 2). Mean change in mRS score also favoured extended-release carbidopa-levodopa (table 2). Mean changes in SF-36 components, EQ-5D scores, and SCOPA-S scores favoured extended-release carbidopalevodopa only on the EQ-5D usual-activities score (table 2). Table 3 shows doses and dosing frequencies of levodopa throughout the study. Compared with the initially recommended extended-release carbidopa-levodopa regimens, 234 patients (60%) required higher doses and 61 patients (16%) required lower doses. At the end of dose conversion, the mean extended-release to immediate-release carbidopa-levodopa dose ratio was 2·05 (SD 0·56; median 1·93, range 0·9–4·7). After randomisation, mean dosing frequency was 3·6 doses per day (SD 0·7) for extendedrelease carbidopa-levodopa versus 5·0 doses per day (1·2) for the immediate-release formulation (p<0·0001). The number of extended-release carbidopa-levodopa capsules taken per day averaged 10·6 (3·0) whereas the number of immediate-release tablets (or half-tablets) taken per day averaged 8·2 (SD 3·6; p<0·0001).

Extended-release carbidopa-levodopa (n=201)

Immediate-release carbidopa-levodopa (n=192)

Baseline

Baseline

End of study

Change from baseline

End of study

Mean difference at end p value* of study (95% CI)

Change from baseline

Patient diary Off-time, percentage of waking day† Off-time, h‡ Responders, ≥1 h improvement

36·88% (13·09) 6·05 (2·26) NA

23·82% (14·91) –13·06% (17·57) 3·87 (2·46) 127 (63%)

–2·18 (2·91) NA

35·99% (11·40) 29·79% (15·81) –6·21% (14·86) 5·89 (1·97)

4·88 (2·71)

NA

87 (45%)

–5·97% (–9·05 to –2·89) <0·0001

–1·01 (2·53)

–1·01 (–1·52 to –0·49)

<0·0001

NA

18% (8 to 28)

<0·0001

On-time without troublesome dyskinesia, h‡

9·96 (2·43)

11·84 (2·96)

1·88 (3·06)

10·10 (2·29)

10·91 (2·82)

0·80 (2·57)

0·93 (0·42 to 1·44)

0·0002

On-time without dyskinesia, h

8·41 (3·31)

10·01 (4·17)

1·60 (3·59)

8·51 (3·01)

9·29 (3·66)

0·78 (3·19)

0·72 (0·09 to 1·36)

0·0264

On-time with non-troublesome dyskinesia, h

1·56 (2·30)

1·83 (2·98)

0·28 (2·34)

1·59 (2·39)

1·61 (2·43)

0·02 (2·68)

0·22 (–0·25 to 0·70)

0·278

On-time with troublesome dyskinesia, h

0·37 (0·93)

0·52 (1·37)

0·15 (1·26)

0·35 (1·00)

0·45 (1·44)

0·10 (1·48)

0·07 (–0·19 to 0·33)

0·6047

0·76 (0·46 to 1·05)

<0·0001

PGI-C and CGI-C PGI-C (all participants)‡

NA

Participants much or very much improved

NA

4·89 (1·36)

NA

NA

NA

NA

CGI-C (all participants)‡

NA

NA

NA

Participants much or very much improved

NA

80 (40%)

NA

NA

26 (14%)

Parts II and III‡

32·32 (14·42)

26·61 (12·85)

Parts I, II, and III

34·14 (14·88)

28·19 (13·37)

–5·71 (10·36)

32·41 (15·24)

30·27 (15·12)

–5·95 (10·69)

34·26 (15·84)

32·22 (15·85)

Total

39·34 (15·18)

32·96 (13·71)

–6·38 (11·38)

39·22 (15·88)

37·00 (16·37)

Part I

1·82 (1·29)

1·58 (1·42)

–0·24 (1·12)

1·85 (1·44)

Part II: on state

9·11 (4·75)

7·79 (4·71)

–1·32 (3·91)

Part II: off state

17·35 (6·80)

16·27 (6·80)

Part III

23·21 (11·47)

Part IV

5·20 (2·15)

77 (38%) 4·95 (1·19)

4·13 (1·33) 33 (17%) 4·31 (1·10)

NA NA

21% (12 to 30)§

NA

0·64 (0·38 to 0·89)

NA

<0·0001§ <0·0001

27% (18 to 35)§

<0·0001§

–2·14 (9·89)

–3·66 (–5·62 to –1·69)

<0·0001

–2·05 (10·44)

–4·03 (–6·08 to –1·98)

<0·0001

–2·22 (11·01)

–4·04 (–6·18 to –1·89)

<0·0001

1·95 (1·69)

0·10 (1·52)

–0·37 (–0·64 to –0·11)

0·0045

8·81 (5·16)

8·60 (5·56)

–0·22 (3·93)

–0·81 (–1·52 to –0·10)

0·003

–1·09 (5·24)

17·14 (6·32)

17·04 (7·03)

–0·09 (4·30)

–0·77 (–1·58 to –0·40)

0·0105

18·83 (9·49)

–4·39 (8·29)

23·60 (11·43)

21·67 (10·89)

–1·92 (7·74)

–2·84 (–4·04 to –1·54)

<0·0001

4·77 (2·59)

–0·43 (2·46)

4·96 (1·86)

4·78 (2·17)

–0·17 (2·00)

0·01 (–0·45 to 0·42)

0·5534

UPDRS

(Continues on next page)

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Extended-release carbidopa-levodopa (n=201)

Immediate-release carbidopa-levodopa (n=192)

Baseline

Baseline

End of study

Change from baseline

End of study

Mean difference at end p value* of study (95% CI)

Change from baseline

(Continued from previous page) PDQ-39 Total

30·56 (15·72)

26·87 (15·85)

–3·76 (12·20)

31·27 (16·98)

29·40 (15·89)

–1·81 (10·68)

–2·53 (–4·59 to –0·48)

0·0345

Mobility

36·03 (22·56)

30·84 (21·40)

–5·19 (16·33)

37·15 (23·62)

36·17 (23·19)

–0·98 (14·58)

–5·33 (–8·13 to –2·53)

0·0017 0·1047

Activities of daily living

37·58 (22·34)

31·76 (21·47)

–5·82 (17·86)

36·02 (22·53)

32·95 (20·67)

–3·07 (16·50)

–1·19 (–4·15 to 1·77)

Emotional wellbeing

28·75 (18·97)

25·85 (19·40)

–2·90 (15·34)

28·39 (21·00)

27·80 (19·42)

–0·58 (15·12)

–1·95 (–4·61 to 0·72)

0·1462

Stigma

28·33 (25·16)

23·81 (23·19)

–4·59 (18·60)

28·44 (26·40)

24·48 (24·01)

–3·96 (17·34)

–0·67 (–3·73 to 2·39)

0·8112 0·9409

Social support

15·19 (18·57)

15·11 (17·94)

–0·08 (15·98)

16·55 (20·45)

16·27 (19·76)

–0·29 (15·53)

–1·16 (–3·95 to 1·63)

Cognition

23·13 (15·20)

22·64 (15·93)

–0·49 (13·89)

26·63 (17·99)

25·15 (16·15)

–1·34 (14·58)

–2·51 (–4·97 to 0·05)

0·4485

Communication

23·75 (19·20)

21·57 (19·56)

–2·18 (16·12)

25·09 (20·66)

24·38 (19·07)

–0·76 (16·48)

–2·81 (–5·72 to 0·10)

0·1881

Bodily discomfort

36·61 (23·11)

31·87 (21·33)

–4·74 (20·98)

38·09 (23·72)

33·98 (21·55)

–4·11 (20·53)

–2·11 (–5·55 to 1·33)

0·3437

Short form-36 health survey Physical component

39·28 (8·52)

40·98 (8·18)

1·70 (7·06)

38·08 (7·99)

39·04 (8·54)

0·96 (5·86)

1·94 (0·76 to 3·12)

0·0609

Mental component

47·37 (10·77)

46·73 (10·83)

–0·63 (9·76)

46·36 (10·93)

45·80 (10·94)

–0·56 (8·73)

0·93 (–0·72 to 2·57)

0·6892

2·12 (0·75)

1·95 (0·71)

–0·17 (0·69)

2·09 (0·75)

2·08 (0·70)

–0·01 (0·69)

–0·13 (–0·24 to –0·02)

0·0061

Modified Rankin scale Score SCOPA-S Use of sleeping tablets

0·58 (1·15)

0·53 (1·09)

–0·05 (0·73)

0·56 (1·12)

0·51 (1·07)

–0·05 (0·61)

0·02 (–0·11 to 0·16)

0·9332

Sleeping at night

4·85 (3·69)

4·46 (3·29)

–0·39 (3·26)

5·08 (3·42)

4·87 (3·37)

–0·21 (3·07)

–0·41 (–0·95 to –0·12)

0·2742

Overall quality of sleep at night

4·70 (1·52)

4·87 (1·45)

0·17 (1·37)

4·68 (1·45)

4·70 (1·46)

0·02 (1·35)

0·17 (–0·06 to 0·41)

0·1846

Sleep during the day or evening

4·25 (3·05)

3·89 (2·82)

–0·36 (2·50)

4·49 (2·90)

4·23 (2·72)

–0·26 (2·74)

–0·34 (–0·77 to 0·09)

0·2622

EQ-5D¶ Mobility

53 (26%)

58 (29%)

NA

49 (26%)

51 (27%)

NA

2% (–7 to 11)§

Self-care

93 (46%)

89 (44%)

NA

90 (47%)

89 (46%)

NA

–2% (–12 to 8)§

0·6122§ 0·6799§

Usual activities

58 (29%)

66 (33%)

NA

46 (24%)

45 (23%)

NA

9% (1 to 18)§

0·0388§

Pain or discomfort

57 (28%)

66 (33%)

NA

50 (26%)

48 (25%)

NA

8% (–1 to 17)§

0·0875§

Anxiety or depression

93 (46%)

94 (47%)

NA

93 (48%)

89 (46%)

NA

0·4% (–9 to 10)§

0·9349§

Your own health state today (VAS)

64·38 (17·50)

68·61 (16·93)

66·28 (16·72)

67·13 (17·21)

1·48 (–1·14 to 4·09)§

0·0632§

3·92 (15·12)

0·56 (14·77)

Data are mean (SD) or n (%), unless otherwise stated. NA=not applicable. PGI-C=patient global impression of change. CGI-C=clinical global impression of change. UPDRS=unified Parkinson’s disease rating scale. PDQ-39=39-item Parkinson’s disease questionnaire. SCOPA-S=scales for outcomes in Parkinson’s disease questionnaire-sleep. EQ-5D=EuroQol-5 dimensions (standardised measure of health status developed by the EuroQol group). VAS=visual analogue scale. *ANCOVA with baseline values as the covariate, unless otherwise stated; p values were based on protocol-specified model and CIs were based on end-of-study mean differences and were not used in significance testing. †Primary efficacy measure. ‡Secondary efficacy measures analysed hierarchically; all other listed measures were additional, preplanned secondary measures. §95% CIs obtained with a binomial difference-in-proportions approach, and p values by comparing end-of-study proportions. ¶N (%) with no problems.

Table 2: Efficacy and quality-of-life results

During the 3 week immediate-release carbidopalevodopa dose-adjustment period, 80 (17%) of 471 patients reported an adverse event. The only adverse event reported by more than 1% of patients was headache (1·3%; six patients). Three patients (1%) discontinued treatment early because of adverse events in this phase of the study. Two patients (<1%) reported three serious adverse events, one of which (hypotension) was regarded as related to study treatment. During the 6 week extended-release carbidopa-levodopa dose-conversion period, 206 (46%) of 450 patients reported an adverse event (table 4). 23 (5%) patients discontinued treatment early because of adverse events in this phase of the study. 14 (3%) patients had 22 serious adverse events, including two deaths; one patient had sudden death and the other patient had renal failure. Six www.thelancet.com/neurology Vol 12 April 2013

of these serious adverse events were regarded as related to study drug: gait disturbance (two patients), dyskinesia (two patients), overdose (one patient), and acute psychosis (one patient). During the 13 week double-blind treatment period, 76 (40%) of 192 patients allocated immediate-release carbidopa-levodopa and 87 (43%) of 201 patients allocated extended-release carbidopa-levodopa reported an adverse event (table 5). In this period, there were three early terminations (1–2%) due to adverse events in each group. 11 (5%) patients in the extended-release carbidopa-levodopa group reported 13 serious adverse events. No individual serious adverse event was reported by more than one patient. In one patient, the serious adverse events (anxiety and acute psychosis) were regarded as related to study drug. Five patients 351

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(3%) in the immediate-release carbidopa-levodopa group reported eight serious adverse events. Three of these events (atrial fibrillation, pneumonia, and respiratory failure) were reported by one patient and were regarded as related to the study drug. Four patients developed positive m-MIDI results during maintenance: one patient receiving extendedrelease carbidopa-levodopa declined to complete the sexual behaviour questionnaire at weeks 9 and 12 and, as per m-MIDI instructions, was regarded as positive Visit 1

Visit 2

Open-label dose adjustment

Visit 5

Visit 6

Open-label conversion to IPX066

Visit 7

Visit 8

Double-blind maintenance

6·5

Discussion Randomisation

6·0

5·5 Mean (SE) daily off-time (h)

for compulsive sexual behaviour; one patient receiving extended-release carbidopa-levodopa tested positive for compulsive sexual behaviour at week 12 and at end of study; one patient receiving extended-release carbidopalevodopa tested positive for gambling at early discontinuation (at week 11); and one patient receiving immediate-release carbidopa-levodopa tested positive for buying disorder at week 12 and at end of study. None of these four patients was taking concomitant dopamine agonists. We noted no clinically relevant treatment-group differences, patterns of abnormal trends, or between-visit changes for blood tests, vital signs, or electrocardiogram results.

5·0

4·5 * †

4·0

†

†

IPX066 Immediate-release carbidopa-levodopa

3·5 0

2

4

6

8

10

12

14

16

18

20

22

End of study

185 181

201 192

Time (weeks) Number at risk IPX066 201 Immediate-release 192 carbidopa-levodopa

201 192

201 192

188 186

188 183

Figure 2: Mean daily off-time throughout the study *p=0·0004 vs immediate-release carbidopa-levodopa group by ANCOVA. †p<0·0001 vs immediate-release carbidopa-levodopa group by ANCOVA.

In this study, extended-release carbidopa-levodopa given a mean of 3·6 times per day reduced mean daily off-time by an extra 1·17 h compared with immediate-release carbidopa-levodopa administered a mean of 5·0 times per day. The beneficial effects of extended-release carbidopalevodopa seemed to be clinically meaningful, as suggested by secondary measures including PGI-C, CGI-C, PDQ-39, and mRS. The results are consistent with those reported in the open-label phase 2 study17 and with the notion that, in patients with Parkinson’s disease and motor fluctuations, maintenance of levodopa plasma concentrations translates into more sustained motor benefit (panel).28–30 In our trial, the final daily levodopa dose of extendedrelease carbidopa-levodopa averaged about twice the final daily levodopa dose of the immediate-release formulation. Although levodopa concentrations were not measured, the known pharmacokinetics of extendedrelease carbidopa-levodopa (about 70% bioavailability compared with immediate-release carbidopa-levodopa by AUC and about 30% for Cmax)17 suggest that total systemic levodopa exposure (AUC) was 30–40% higher for extended-release carbidopa-levodopa than for immediaterelease carbidopa-levodopa in this study, with similar peak levodopa concentrations. Because patients enrolled

Treatment (number of patients)

Baseline (day 1)

Levodopa dose, mg per day

Levodopa dosing frequency, doses per day

Median (IQR)

Median Mean (SD) (IQR)

Mean (SD)

Immediate-release carbidopa-levodopa (469 patients)*

750 (500–1000)

794·3 (364·2)

5 (4–6)

5·1 (1·7)

End of immediate-release carbidopa- Immediate-release carbidopa-levodopa (448 patients)† levodopa dose adjustment (week 3)

800 (550–1000)

825·4 (360·4)

5 (4–6)

5·2 (1·7)

1365 (1140–1960) 1621·7 (744·3)

3 (3–4)

3·6 (0·7)

814·5 (341·2)

5 (4–6)

5·0 (1·2)

1330 (1140–1960) 1630·0 (760·4)

3 (3–4)

3·6 (0·7)

End of extended-release carbidopa- Extended-release carbidopa-levodopa (393 patients)‡ levodopa dose conversion (week 9) Randomisation (week 9)§

Immediate-release carbidopa-levodopa (192 patients)

Randomisation (week 9)§

Extended-release carbidopa-levodopa (201 patients)

800 (550–1000)

*Dosing data for 469 participants.†Dosing data for 448 participants. ‡393 participants completed dose conversion and were randomly allocated to double-blind maintenance phase. §Includes only patients remaining in the study who were randomly allocated to treatment groups.

Table 3: Levodopa dosages and dosing frequencies

352

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in this study were required at entry to have a substantial amount of off-time despite their immediate-release carbidopa-levodopa therapy, a greater levodopa AUC (and hence a greater levodopa daily dose) from extendedrelease carbidopa-levodopa would be expected to be required to ameliorate levodopa troughs and reduce offtime. That on-time with troublesome dyskinesia was not significantly different between groups suggests that levodopa peaks were not substantially increased and extended-release carbidopa-levodopa dosing was clinically appropriate. Nonetheless, we cannot completely exclude the possibility that some of the potential benefits observed for extended-release carbidopa-levodopa could have been due to increased levodopa systemic exposure. Although extended-release carbidopa-levodopa was dosed less frequently throughout the day than was immediate-release carbidopa-levodopa, the extendedrelease regimen did require administration of more pills on average in this study. This limitation was partly due to physical issues regarding how much carbidopa-levodopa in bead form can fit into capsules of reasonable size and partly due to the fact that the study allowed only two dose strengths during dose conversion and only one dose strength during the maintenance phase. However, these clinical trial constraints will not be present in clinical practice. Moreover, for most patients with substantial motor fluctuations, the key aspect of the drug regimen is the dosing frequency rather than the number of pills required.31 Only one patient of 450 (<1%) reported difficulty swallowing extended-release carbidopalevodopa capsules during the dose-conversion phase. Extended-release carbidopa-levodopa was generally well tolerated. During the open-label extended-release carbidopa-levodopa dose-conversion period, 23 patients (5%) withdrew because of adverse events and 13 patients (3%) withdrew because of a lack of efficacy. Most of the adverse events reported during dose conversion were to be expected with adjustment of dopaminergic therapy. During the 13 week double-blind maintenance period, the overall adverse event reporting rates were much the same for the two groups (43% for extended-release carbidopa-levodopa vs 40% for immediate-release formulation). During the double-blind maintenance period, 15 patients (7%) randomly allocated extendedrelease carbidopa-levodopa withdrew from the study compared with ten patients (5%) randomly allocated immediate-release carbidopa-levodopa. Efficacy and tolerability of extended-release carbidopa-levodopa might be improved further through the use of a longer dose conversion period or the ability to combine more than one dose strength of extended-release carbidopalevodopa. However, this suggestion is speculative. A limitation of this study was that dose adjustment of immediate-release carbidopa-levodopa and dose conversion to extended-release carbidopa-levodopa before randomisation were done sequentially in an open-label manner. This method was implemented because difwww.thelancet.com/neurology Vol 12 April 2013

Patients with adverse events ≥1 adverse event

206 (46%)

Dyskinesia

25 (6%)

Nausea

24 (5%)

Headache

19 (4%)

Dizziness

17 (4%)

On and off phenomenon

14 (3%)

Fall

12 (3%)

Dry mouth

11 (2%)

Anxiety

11 (2%)

Insomnia

11 (2%)

Constipation

9 (2%)

Data are number of patients (%). Adverse events were coded according to the Medical Dictionary for Regulatory Activities version 12.1.

Table 4: Treatment-emergent adverse events reported by ≥2% of 450 patients during the open-label dose conversion

Extendedrelease carbidopalevodopa (n=201)

Immediaterelease carbidopalevodopa (n=192)

Insomnia

7 (3%)

2 (1%)

Nausea

6 (3%)

3 (2%)

Fall

6 (3%)

4 (2%)

Dizziness

5 (2%)

2 (1%)

Dyskinesia

5 (2%)

2 (1%)

Diarrhoea

4 (2%)

1 (1%)

Peripheral oedema

4 (2%)

4 (2%)

Upper respiratory tract infection

4 (2%)

4 (2%)

Urinary tract infection

4 (2%)

4 (2%)

Sleep disorder

4 (2%)

4 (2%)

Weight decreased

4 (2%)

0

Back pain

3 (1%)

4 (2%)

Arthralgia

2 (1%)

4 (2%)

Vomiting

1 (<1%)

4 (2%)

Depression

1 (<1%)

5 (3%)

Data are number of patients (%). Adverse events were coded according to the Medical Dictionary for Regulatory Activities version 12.1.

Table 5: Treatment-emergent adverse events reported by ≥2% of patients in either treatment group during the double-blind maintenance period

ferences between the pharmacokinetic profiles of the drugs make double-dummy dose titration impractical. In the phase 2 study,17 plasma levodopa concentrations of extended-release carbidopa-levodopa and immediaterelease carbidopa-levodopa rose at a similarly rapid rate and were sustained above 50% of peak concentration for 4 h with extended-release carbidopa-levodopa versus 1·4 h with immediate-release carbidopa-levodopa (p<0·0001). Therefore, if, for example, immediate-release carbidopalevodopa were initially provided five times per day on an every 3 h schedule and extended-release carbidopalevodopa were administered three times per day on an 353

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every 6 h schedule in a double-dummy design, it might be inadvisable to adjust extended-release carbidopa-levodopa to every 3 h if a patient were wearing off every 2·5 h, because this regimen could lead to levodopa accumulation through the day and excessive dyskinesia. The different durations of immediate-release carbidopa-levodopa dose adjustment (3 weeks) and extended-release carbidopa-levodopa dose conversion (6 weeks) were also a potential limitation. However, patients were required to be on the immediate-release carbidopa-levodopa for at least 4 weeks before study entry and most were on it much longer, averaging about 6 years. Nonetheless, whether immediate-release regimens could have been improved further is not known. Higher immediate-release doses or more frequent administrations might have reduced off-time further in this treatment group. Alternatively, increases in immediate-release doses might have induced or exacerbated dyskinesia or other adverse events. Importantly, at the end of the dose-adjustment period, patients were already receiving immediate-release carbidopa-levodopa five times per day (on average), and there might be a practical limit as to how often it can be administered before problems related to inconvenience and non-compliance become manifest.32 Panel: Research in context Systematic review IPX066 is an oral, extended-release capsule containing beads of carbidopa and levodopa that dissolve at various rates to produce both immediate-release and multiple delayedrelease effects. Its overall pharmacokinetic characteristics are distinct from those of carbidopa-levodopa administered orally in standard immediate-release form, as a controlled-release formulation, or as a formulation designed for enhanced gastrointestinal solubility. We did a PubMed search on Jan 12, 2013, with the search terms “IPX066” and “clinical trial”, without restriction on date of publication or language restriction, and identified 97 papers. However, only one identified publication was an extended-release carbidopa-levodopa trial17—more specifically, an open-label phase 2 crossover study of extended-release carbidopa-levodopa versus immediate-release carbidopa-levodopa (8 days of each treatment) in patients with motor complications in Parkinson’s disease.17 Interpretation Our double-blind 13 week phase 3 comparison of extended-release carbidopa-levodopa and standard immediate-release carbidopa-levodopa in Parkinson’s disease patients with motor fluctuations on levodopa extends the findings of the phase 2 study. Our results suggest that many such patients can be switched from standard immediate-release carbidopa-levodopa to extended-release carbidopa-levodopa taken less frequently (eg, three or four times per day instead of four or five times per day), with reduced off-time, improved motor function, improved functionality, and improvement in at least some measures of quality of life. Future trials in patients with Parkinson’s disease and motor fluctuations might assess conversion from immediate-release carbidopa-levodopa to extended-release carbidopa-levodopa versus addition of adjunctive drugs such as monoamine oxidase-B inhibitors, catechol O-methyltransferase-inhibitors, dopamine agonists, or amantadine. Additional studies will be needed to assess whether use of extended-release carbidopa-levodopa rather than immediate-release carbidopa-levodopa when levodopa is first introduced in early Parkinson’s disease might lead to less development of dyskinesia over time.

354

During the double-blind maintenance period, patients might have recognised their assigned drug on the basis of what they had received during the open-label doseadjustment phases. This recognition could potentially have led to augmentation of the reported response. Notably, 57 (13%) of 450 patients did not complete the open-label transition from immediate-release carbidopalevodopa to extended-release carbidopa-levodopa, and 78 (17%) of 471 patients who entered the study did not reach the randomisation point. In clinical practice, some patients will be unable to tolerate the transition from immediate-release to extended-release carbidopalevodopa, and whether the percentage will be higher or lower than what we have reported is unknown. The overall generalisability of our results to the entire population of Parkinson’s disease patients with motor fluctuations is also not clear, especially if patients not meeting the eligibility criteria used in our study are considered for treatment. Impulse control disorders occur in around 13·6% of Parkinson’s disease patients who are taking dopamine agonists, associating these drugs with a 2–3·5-times greater prevalence of such disorders than was noted in Parkinson’s disease patients not taking dopamine agonists.33 Levodopa is also associated with an increased risk of impulse control disorders (although not as high as for dopamine agonists) and the risk might be doserelated.33 In our study, we identified four patients who developed impulse control disorders (1% of 471 patients), three in patients taking extended-release carbidopa-levodopa (1% of 450 patients exposed to the extended-release study drug at any point) and one in a patient taking immediate-release carbidopa-levodopa (<1% of 471 patients exposed to the immediate-release study drug at any point), and none of these patients was on dopamine agonists. With a longer observation period, more patients might develop impulse control disorders. Whether extended-release carbidopalevodopa confers an increased risk of impulse control disorder compared with immediate-release carbidopalevodopa is unknown, and as with all patients with Parkinson’s disease who are treated with levodopa or dopamine agonists, individuals treated with extendedrelease carbidopa-levodopa should be warned about the possibility of impulse control disorders and should be monitored clinically. For patients with Parkinson’s disease and motor fluctuations on immediate-release carbidopa-levodopa, treatment options might include increasing the dose, administering it more frequently, or adding adjunctive medications such as monoamine oxidase-B inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, or amantadine.34,35 Further trials will be needed to understand how conversion to extended-release carbidopa-levodopa compares with these alternative treatment options. Extended-release carbidopa-levodopa has been associated with a greater reduction in off-time www.thelancet.com/neurology Vol 12 April 2013

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than carbidopa-levodopa plus entacapone.36,37 On the basis of available evidence, we speculate that conversion from immediate-release to extended-release carbidopalevodopa in patients with Parkinson’s disease and motor fluctuations might provide a reduction in off-time similar to or greater than that attained by adding a monoamine oxidase-B inhibitor and be similarly well tolerated. A key difference is that conversion to extended-release carbidopa-levodopa allows a significant reduction in levodopa dosing frequency. Adding a dopamine agonist to an immediate-release carbidopa-levodopa regimen might afford a greater reduction in off-time but no reduction in levodopa dosing frequency, and is likely to be associated with a heightened risk of adverse events such as impulse control disorders, hallucinations, oedema, somnolence, and sudden-onset sleep.34 It is also important to note that the benefits we observed in switching patients from immediate-release to extendedrelease carbidopa-levodopa occurred in a population in which about half were already taking a dopamine agonist and about a quarter were already taking a monoamine oxidase-B inhibitor. In this phase 3 study, extended-release carbidopalevodopa, administered at a reduced dosing frequency, provided similar tolerability and showed superior efficacy compared with the current standard of care, immediaterelease carbidopa-levodopa. Extended-release carbidopalevodopa significantly reduced off-time, increased on-time without troublesome dyskinesia, and improved UPDRS scores. The benefits of extended-release carbidopa-levodopa seemed to be clinically meaningful, as assessed by PGI-C, CGI-C, PDQ-39, and mRS. The results of this study suggest that extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson’s disease and motor fluctuations on immediate-release carbidopa-levodopa. Contributors RAH contributed to study conception and design, acquisition of data, and analysis and interpretation of data, drafted and edited the manuscript, and approved the final version for publication. AH contributed to study design, dose conversion table and guidance, endpoint selection, data analysis and interpretation, study report, manuscript writing and editing, and literature research. SK contributed to study design, endpoint selection, study conduct, data analysis and interpretation, study report, manuscript writing and editing, and safety data collection and analysis. AJE, KS, MS, and WO assisted with acquisition of data, analysis and interpretation of data, and revision of manuscript. MO’C assisted with data management and statistical analysis. SG contributed to study design, conduct, analyses, and reporting. Conflicts of interest RAH has received honoraria or payments for consulting, advisory services, speaking services in the past 12 months from Abbott Laboratories, Allergan, AstraZeneca, Ceregene, Chelsea Therapeutics, GE Healthcare, Impax Laboratories, Ipsen Biopharmaceuticals, Lundbeck, Med-IQ, Merck/MSD, Noven Pharmaceuticals, Straken Pharmaceuticals, Targacept, Teva Pharmaceuticals Industries, Teva Neuroscience, Upsher-Smith Laboratories, UCB, UCB Pharma SA, XenoPort. RAH’s institution has received research support in the past 12 months from Abbott Laboratories, Addex Therapeutics, Allergan, AstraZeneca, Chelsea Therapeutics, GE Healthcare, Impax Laboratories, Ipsen Biopharmaceuticals, Merck/MSD, Merz, the

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Michael J Fox Foundation for Parkinson’s Research, Schering-Plough, Teva Neuroscience, UCB, Vita-Pharm. RAH has received royalties in the past 12 months from the University of South Florida (FL, USA). In addition, RAH has consulted in litigation with lawyers representing various current and former manufacturers of welding consumables. AH, SK, MO’C, and SG are employees and stockholders of Impax Laboratories. AJE has received grants from the CleveMed/Great Lakes Neurotechnologies, Davis Phinney Foundation, the Michael J Fox Foundation, and the US National Institutes of Health (NIH; 1K23MH092735); he has received royalties from Lippincott Williams & Wilkins and from Cambridge University Press; he has been a consultant for Chelsea Therapeutics; and has been on the Advisory Board for Abbott Laboratories, Chelsea Therapeutics, Eli Lilly, Impax Laboratories, Merz Pharmaceuticals, Solstice Neurosciences, Solvay Pharmaceuticals, and Teva Pharmaceuticals; he has received honoraria from American Academy of Neurology, the Movement Disorders Society, Novartis Pharmaceuticals, and UCB Pharma. KS is a part-time employee of Merz Pharmaceuticals; he has received grant support from Abbott Laboratories, Acadia Pharmaceuticals, NIH, and Teva Pharmaceuticals; and he has stock ownership from Elan Pharmaceuticals; he is a consultant and/or speaker for Adamas Pharmaceuticals, Impax Laboratories, Synosia Therapeutics, and Teva Pharmaceuticals. MS has received grant/research support from Ceregene, Impax Laboratories, the Michael J Fox Foundation, NIH, Novartis Pharmaceuticals, and the Parkinson Study Group; he has been a consultant for Allergan, Chelsea Therapeutics, General Electric, GlaxoSmithKline, Merck, Merz Pharmaceuticals, NeuroNova AB, Novartis Pharmaceuticals, Noven Pharmaceuticals, Ossmotica Pharmaceutical, SK-Life Sciences, Teva Pharmaceuticals, and UCB Pharma; he is on the Protocol Steering Committee for Allergan, EMD Serono, and Teva Pharmaceuticals; he has received royalties from Informa Press. WO has received speaking and consulting fees from Allergan, GlaxoSmithKline, Ipsen, H Lundbeck A/S, Merz Pharmaceuticals, Teva Pharmaceuticals, and UCB Pharma. Acknowledgments Linnéa Elliott from The Curry Rockefeller Group (Tarrytown, NY, USA) provided editorial support, funded by Impax Laboratories. References 1 Jankovic J, Stacy M. Medical management of levodopa-associated motor complications in patients with Parkinson’s disease. CNS Drugs 2007; 21: 677–92. 2 Scheife RT, Schumock GT, Burstein A, Gottwald MD, Luer MS. Impact of Parkinson’s disease and its pharmacologic treatment on quality of life and economic outcomes. Am J Health Syst Pharm 2000; 57: 953–62. 3 Dodel RC, Berger K, Oertel WH. Health-related quality of life and healthcare utilisation in patients with Parkinson’s disease: impact of motor fluctuations and dyskinesias. Pharmacoeconomics 2001; 19: 1013–38. 4 Findley LJ, Lees A, Apajasalo M, Pitkänen A, Turunen H. Cost-effectiveness of levodopa/carbidopa/entacapone (Stalevo) compared to standard care in UK Parkinson’s disease patients with wearing-off. Curr Med Res Opin 2005; 21: 1005–14. 5 Politis M, Wu K, Molloy S, Bain PG, Chaudhuri KR, Piccini P. Parkinson’s disease symptoms: the patient’s perspective. Mov Disord 2010; 25: 1646–51. 6 Ahlskog JE, Muenter MD, McManis PG, Bell GN, Bailey PA. Controlled-release Sinemet (CR-4): a double-blind crossover study in patients with fluctuating Parkinson’s disease. Mayo Clin Proc 1988; 63: 876–86. 7 Hutton JT, Morris JL, Roman GC, Imke SC, Elias JW. Treatment of chronic Parkinson’s disease with controlled-release carbidopa/ levodopa. Arch Neurol 1988; 45: 861–64. 8 Jankovic J, Schwartz K, Vander Linden C. Comparison of Sinemet CR4 and standard Sinemet: double-blind and long-term open trial in parkinsonian patients with fluctuations. Mov Disord 1989; 4: 303–09. 9 Lieberman A, Gopinathan G, Miller E, Neophytides A, Baumann G, Chin L. Randomized double-blind cross-over study of Sinemet controlled release (CR4 50/200) versus Sinemet 25/100 in Parkinson’s disease. Eur Neurol 1990; 30: 75–78.

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