Long-Term Selegiline Monotherapy for the … Selegiline...(UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile,

ORIGINAL ARTICLE

Long-Term Selegiline Monotherapy for the Treatmentof Early Parkinson Disease

Yoshikuni Mizuno, MD,* Nobutaka Hattori, MD,* Tomoyoshi Kondo, MD,† Masahiro Nomoto, MD,‡Hideki Origasa, PhD,§ Ryosuke Takahashi, MD,|| Mitsutoshi Yamamoto, MD,¶ and Nobuo Yanagisawa, MD#

Objectives: The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patientswith early Parkinson disease (PD).Methods: We conducted a 56-week prospective study in patients withearly PD (N = 134) who had previously completed the randomized,double-blind, placebo-controlled phase III trial of selegiline monotherapyfor 12 weeks. In the present study, dosing was titrated from 2.5 to10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week,the dosagewas maintained at 10 mg/d until week 56. The primary outcomewas any change in the total Unified Parkinson's Disease Rating Scale(UPDRS) score (part I + II + III) from baseline. Secondary outcomes,including changes in the UPDRS subscores and safety profile, werealso evaluated.Results: Ninety-one (67.9%) patients completed the 56-week study.Treatment with selegiline significantly reduced total UPDRS scorefrom week 4 (mean ± SD, −2.62 ± 3.83; P < 0.0001) to week 56(−3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20(−5.79 ± 5.57; P < 0.0001). In addition, we found similar improve-ments in the UPDRS parts II and III scores. The incidence rate of ad-verse drug reactions was 44.3% (58 patients) and did not increaseduring the period of 10 mg selegiline administration.Conclusions: Long-term monotherapy with selegiline (10 mg/d) was ef-fective and well tolerated in patients with early PD in this 56-week study.

KeyWords: Parkinson disease, selegiline, long-term study, monotherapy,side effects

(Clin Neuropharm 2019;00: 00–00)

C urrently, there is no cure for Parkinson disease (PD); how-ever, medications and medical devices that control the symp-

toms are available. Medications, such as levodopa, dopamineagonists, and monoamine oxidase type B (MAO-B) inhibitors(selegiline or rasagiline), have been recommended for early treat-ment of de novo patients with PD.1–3 There is sufficient evidenceof the safety and efficacy of long-term use of selegiline with orwithout levodopa.4–13 In Japan, selegiline was approved for com-bination use with levodopa at a recommended dose of 7.5 mgselegiline in 1998, and data on the safety and efficacy of the com-bination therapy have been accumulating to date. Selegiline has

*Department of Neurology, Juntendo University School of Medicine, Tokyo;†Rehabilitation Hananoie Hospital, Tochigi; ‡Department of Neurology andClinical Pharmacology, Ehime University Graduate School of Medicine,Ehime; §Department of Biostatistics and Clinical Epidemiology, GraduateSchool of Medicine and Pharmaceutical Sciences, University of Toyama, To-yama; ||Department of Neurology, Kyoto University Graduate School of Medi-cine, Kyoto; ¶Takamatsu Neurology Clinic, Takamatsu; and #All Japan LaborWelfare Foundation, Tokyo, Japan.This study was funded by FP Pharmaceutical Corporation.Address correspondence and reprint requests to Dr Yoshikuni Mizuno,

Department of Neurology, Juntendo University School of Medicine, 2-1-1HongoBunkyo-ku, Tokyo 113-0033, Japan; E‐mail: [email protected]

Conflicts of Interest and Source of Funding: The authors have no conflicts ofinterest to declare.

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been approved as a monotherapy with a maximum dose of10 mg in other countries, however not for patients with early PDin Japan, and its efficacy and safety have not been investigated.Therefore, we conducted a phase III trial14 and the present56-week prospective study to evaluate the efficacy and safety of10 mg selegiline as a monotherapy for Japanese patients in theearly stages of PD. In this study, we report the results of theopen-label, long-term (up to 56 weeks) study aimed at evaluatingthe efficacy and safety of selegiline monotherapy in patients withearly PD.

MATERIALS AND METHODS

PatientsThe eligibility criterion for the present open-label study was

patients who had completed the previous double-blind phase IIIclinical trial, which included 292 patients with early PD whohad been randomly assigned to receive placebo or selegiline treat-ment alone. In this long-term study, patients were enrolled if theycould attend all scheduled visits, receive scheduled tests, and pro-vide informed consent. Patients were excluded from the study ifthey had received any drugs contraindicated to selegiline, suchas pethidine and tricyclic antidepressants, after the initiation ofthe phase III trial, or if they were women who were pregnant,lactating, or willing to become pregnant during the study. Somepatients were also excluded due ineligibility that was decidedby the investigators. In addition, patients could not use otherantiparkinsonian medications, including levodopa or contrain-dications to selegiline (such as pethidine), during the study.

Study DesignThiswas a 56-week, open-label, prospective study conducted

from April 2012 to July 2014 at 42 clinical institutions in Japan inaccordance with Good Clinical Practice. The study was approvedby the institutional review boards according to the principles de-scribed in the Declaration of Helsinki.

Administration of selegilinewas started at a dose of 2.5 mg/dand titrated up to 10 mg/d in increments of 2.5 mg/d for 2 weeks.From week 7, administration of selegiline was maintained at adose of 10 mg/d until week 56. The daily regimen consisted of2.5 mg after breakfast during weeks 1 to 2, 2.5 mg twice daily af-ter breakfast and lunch during weeks 3 to 4, 5 mg after breakfastand 2.5 mg after lunch during weeks 5 to 6, and 5 mg twice dailyafter breakfast and lunch during weeks 7 to 56.

Outcome MeasuresThe primary outcome measure was any change in the total

Unified Parkinson's Disease Rating Scale (UPDRS) score (partI + II + III) from baseline. Secondary outcome measures includedchanges in (1) the UPDRS part II + III score, (2) any of the 4UPDRS subscales from baseline, and (3) the proportion of re-sponders who had achieved a greater than 20%, greater than

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Mizuno et al Clinical Neuropharmacology • Volume 00, Number 00, Month 2019

25%, or greater than 30% reduction in the total UPDRS scores atthe final visit. In addition, we examined other secondary outcomemeasures, including modified Hoehn and Yahr (H/Y) stage ateach visit, and Clinical Global Impression of Improvement(CGI-I) scores at week 28 and the final visit. Safety assessmentswere measured using the number of adverse events (AEs), vitalsigns, electrocardiogram results, and laboratory tests.

Post hoc analyses included changes in UPDRS-tremor (items16, 20, and 21; range, 0–32), UPDRS-rigidity (item 22; range,0–20), UPDRS-bradykinesia (items 23–26 and 31; range, 0–36),and UPDRS–postural instability and gait disturbances (PIGD)(items 13–15, 29, and 30; range, 0–20) scores. Further post hocanalyses were conducted on the integrative data from the phaseIII trial and this long-term study with respect to changes in the to-tal UPDRS score.

Statistical AnalysisStatistical analyses were performed using SAS software 9.2

(TS2M3, SAS Institute Inc, Cary, North Carolina).15 Allefficacy analyses were performed on the full analysis set, whichincluded all subjects who had received at least 1 dose of selegilineand had recorded at least 1 posttreatment efficacy measurement.If there were any missing values, the last observation carriedforward imputation method was applied. All the safety analyseswere conducted on the safety population, which included patientswho had received at least 1 dose of selegiline and recorded atleast 1 safety measurement. The primary and secondary efficacymeasurements from all study visits (except the modified H/Yscale, CGI-I, and a proportion of responders) were compared with

FIGURE 1. Flowchart showing the screening, enrollment, and final num

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measurements at baseline using the Dunnett test.16 Measurementsat the final visit were compared using paired t tests. The modifiedH/Y stage and CGI-I scores were indicated with numbers andpercentages of patients in the respective categories. In the posthoc integrative data analyses, total UPDRS score at baselinefrom the phase III trial was compared between groups usingindependent t tests. Differences in the changes from baselinein total UPDRS scores at week 12 in the phase III trial, or atweek 0 in the present study, were evaluated between the phaseIII–placebo and phase III–selegiline groups by analysis ofcovariance. Results are expressed as mean ± SD, and a P valueof <0.05 was considered to be statistically significant.

RESULTS

PopulationOne hundred thirty-six patients consented to take part in the

study and were screened after completion of the phase III trial(Fig. 1). Two patients dropped out before their enrollment or initi-ation of the treatment. After initiation of the selegiline treatment,43 patients were excluded because of the following reasons: dis-ease progression (n = 16), participation refusal or consent with-drawal (n = 11); AEs (n = 5), contraindications (n = 4), andothers (n = 7). As a whole, 67.9% (91/134) of patients completedthe 56-week study (Fig. 2). The safety population and full analysisset analyses were performed on 131 patients, including those whohad discontinued after initiation of the therapy. Three patientswere excluded after the study due to Good Clinical Practice viola-tion. The baseline characteristics of the patients are presented in

bers of patients in each group.

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FIGURE 2. Proportion of patients who continued participating in the study. The total number of patients included in the final evaluation is 134.

Clinical Neuropharmacology • Volume 00, Number 00, Month 2019 Selegiline for Early Parkinson Disease

Table 1. The mean total UPDRS score and modified H/Y stageof all patients included in this study were 23.2 ± 11.3 and2.0 ± 0.6, respectively.

TABLE 1. Patient Demographics at Baseline

Patients Characteristics N = 131

SexMale 60 (45.8)Female 71 (54.2)

Age, yMean 63.6 ± 8.320–29 0 (0.0)30–39 3 (2.3)40–49 6 (4.6)50–59 20 (15.3)60–69 68 (51.9)≥70 34 (26.0)

UPDRS scorePart I 0.4 ± 0.9Part II 5.5 ± 3.3Part III 17.3 ± 8.7Part IV 0.2 ± 0.4Part I + II + III 23.2 ± 11.3Part II + III 22.8 ± 10.9

Modified H/Y stageMean 2.0 ± 0.61 19 (14.5)1.5 8 (6.1)2 67 (51.1)2.5 20 (15.3)3 17 (13.0)

Each value represents the number of patients (percentage) or mean ± SD.



Efficacy

Selegiline monotherapy led to a significant reduction in totalUPDRS score (the primary outcome measure) from week 4(−2.62 ± 3.83; P < 0.0001) to week 56 (−3.39 ± 9.27; P < 0.01)or the final visit (−2.63 ± 8.32; 95% confidence interval, −4.071to −1.183; P < 0.05) when compared with the baseline score(Fig. 3). A significant reduction in the primary outcome measureat week 4 was achieved with a selegiline dosage of 7.5mg/d. Afterselegiline was titrated up to 10 mg/d, further reduction was ob-served at week 8 (−4.39 ± 4.76), with a peak effect seen at week20 (−5.79 ± 5.57; P < 0.0001). A similar trend was observed forboth UPDRS parts II and III scores; however, there was no signif-icant decrease in UPDRS part I scores at all time points.

The proportion of responders who achieved a greater than20%, greater than 25%, and greater than 30% reduction in totalUPDRS scores were 45.4%, 40.8%, and 35.4%, respectively(Table 2). There was an increase in the proportion of patients withmodified H/Y stage 0–2 from baseline (71.8%) to week 24(79.5%), followed by a decrease from week 32 (79.2%) to the fi-nal evaluation (70.8%), which was similar to the primary outcomemeasure results (Fig. 4). There was an increase in the proportionof patients with modified H/Y stage 1 from baseline (14.5%) toweek 56 (27.0%) or the final visit (22.3%). In contrast, therewas no increase in the proportion of patients with modified H/Ystage 2.5, 3, 4, or 5 from baseline (28.2%) until week 56 (24.7%)or the final visit (29.2%). The changes in CGI-I score from baselineat week 28 or the final evaluation are reported in Figure 5. The com-bined proportion of patients rated as “very much improved” and“much improved” were 43.7% (52/119) and 31.7% (38/120) atweek 28 and the final evaluation, respectively.

Post hoc analyses assessed the efficacy for each cardinal PDsymptom with the UPDRS subscales (Fig. 6). There was a signif-icant decrease in changes from baseline in the UPDRS-tremorscore from week 4 (−0.481 ± 1.218; P < 0.0001) to the final visit(−0.447 ± 1.936; P < 0.05), except in week 56 (−0.421 ± 2.144).In addition, there were significant decreases in the changes frombaseline in the UPDRS-rigidity score from week 4 (−0.58 ± 1.215;




FIGURE 3. Mean changes in the total UPDRS and UPDRS parts I, II, and III scores from baseline. A, Total UPDRS score; (B) changes in theUPDRS part I score; (C) changes in the UPDRS part II score; and (D) changes in the UPDRS part III score. Data are expressed as mean ± SD(N = 131). Statistically significant versus baseline *P < 0.05, †P < 0.01, ‡P < 0.001, §P < 0.0001 by Dunnett test, ¶P < 0.05 by paired t test.

TABLE 2. Proportion of Responders Achieving ≥20%, ≥25%, or≥30% Reduction in the Total UPDRS Score

Reduction in the Total UPDRSI + II + III Score Responder Nonresponder

≥20% 59 (45.4) 71 (54.6)≥25% 53 (40.8) 77 (59.2)≥30% 46 (35.4) 84 (64.6)

Each value represents the number of patients (percentage).

Patients evaluated: n = 130.


P < 0.0001) to the final visit (−0.626 ± 1.903; P < 0.05), except inweek 52 (−0.708 ± 2.191). We found significant decreases in thechanges from baseline in the UPDRS-bradykinesia score from week4 (−0.985 ± 1.784; P < 0.0001) to the final visit (−0.962 ± 3.004;P < 0.05). Finally, we found significant decreases in the changes inUPDRS-PIGD scores from baseline from week 4 (−0.229 ± 0.819;P < 0.01) to week 20 (−0.397 ± 1.054; P < 0.05). The maximumeffect in these 4 items was observed at week 20 (Fig. 6), whichwas in line with the maximum effect found in the total UPDRS,UPDRS part II, and UPDRS part III scores (Fig. 3).

We implemented this study with patients who had completedthe phase III trial and performed the integrative data analyses on thesestudies as post hoc analyses (Fig. 7). We analyzed 131 patients in thelong-term study that were randomly allocated to the placebo (n = 63)or selegiline (phase III–selegiline, n = 68) groups from the phaseIII trial. The washout periods of the phase III–placebo and phaseIII–selegiline groups were 18.89 ± 9.30 (range, 6–63 days; me-dian, 15 days) and 18.51 ± 10. 65 (range, 8–85 days; median,15 days) days, respectively.

The total UPDRS scores of the phase III–selegiline andphase III–placebo groups at baseline were 25.66 ± 10.15 and24.86 ± 10.71, respectively (P = 0.6596). At week 12 in the phaseIII trial, there was a significantly greater change from baseline inthe total UPDRS score of the phase III–selegiline group(−7.07 ± 7.73, n = 67) compared with the phase III–placebo group(−3.98 ± 6.24, n = 63), as shown in Figure 7 (P = 0.0151). At theend of the phase III washout period, there was a significant differ-ence in the change from baseline in the total UPDRS score be-tween the phase III–selegiline (−3.71 ± 5.82, n = 68) and phaseIII–placebo (−0.33 ± 4.91, n = 63; P = 0.0006) groups. Further-more, this difference remained until week 28 of the selegilinetreatment, but not up to week 56 (Fig. 7).



Safety

The incidence rate of adverse drug reactions (ADRs) was44.3% (58/131 patients). Adverse drug reactions with an inci-dence rate of 2% or greater are shown in Table 3. The most com-mon ADRs were insomnia (5.3%, 7/131), constipation (4.6%, 6/131), increased blood creatine kinase (3.8%, 5/131), back pain(3.1%, 4/131), hypertension (3.1%, 4/131), vomiting (2.3%, 3/131), falls (2.3%, 3/131), decreased white blood cell count(2.3%, 3/131), somnolence (2.3%, 3/131), and orthostatic hypo-tension (2.3%, 3/131). Adverse drug reaction incidence rates didnot increase during the administration of 10 mg selegiline (weeks9–56; Table 4). Five patients discontinued treatment because ofthe following AEs: anxiety disorder (n = 1), rash (n = 1), halluci-nations (grade 2; n = 1), disturbances in attention (grade 3; n = 1),and sudden death (grade 5; n = 1). Death and other serious AEswere observed in 6 patients [including the sudden death notedabove that led to treatment discontinuation; loss of consciousness




FIGURE 4. Proportion of patients at each modified H/Y scale stage. The number of patients analyzed at each time point is indicated inparentheses.


accompanying orthostatic hypotension (n = 1); thoracic com-pression fracture (n = 1); prostate hypertrophy (n = 1); externalinguinal hernia (n = 1); and stomach cancer (n = 1)]. All AEs, ex-cept sudden death and loss of consciousness accompanying or-thostatic hypotension, were not attributed to selegiline. Anychanges in medical measurements, such as laboratory tests, vitalsigns, and electrocardiogram, from baseline were not consideredclinically meaningful.

DISCUSSIONLong-term treatment with 10 mg of selegiline increased effi-

cacy up to week 56 in terms of the primary end point when com-pared with baseline scores, by relieving the typical symptoms of

FIGURE 5. Proportion of responder as per CGI-I ratings. Data are repres



PD: tremor, rigidity, bradykinesia, and PIGD. Long-term treatmentwith 10 mg of selegiline was well tolerated, and there was no in-crease in ADRs in weeks 9 to 56. From 134 randomized patients,91 (67.9%) completed the 56-week study. The efficacy and tolera-bility of 56 weeks of monotherapy with 10 mg selegiline in patientswith early PD were comparable to the phase III double-blind,placebo-controlled trial of selegilinemonotherapy in Japan14 or ran-domized placebo-controlled studies in other countries.8–10,12,13

In the present study, the maximum treatment effect, as mea-sured by a 5.79-point reduction in total UPDRS score, was seenat week 20. Previous studies have reported that a greater than3.5 point change in total UPDRS score has clinical importance17;the efficacy of selegiline in this long-term study is clinically im-portant and statistically significant. A similar maximum change

ented as percentage of patients.




FIGURE 6. Mean changes in cardinal symptoms from baseline as measured by the UPDRS score. Cardinal symptoms: tremor, rigidity,bradykinesia, and postural instability/gait disturbance. A, Mean changes in UPDRS tremor–related score. B, Mean changes in UPDRSrigidity–related score. C, Mean changes in UPDRS bradykinesia–related score. D, Mean changes in UPDRS postural instability/gaitdisturbance–related score. Data are expressed as mean ± SD (N = 131). Statistically significant versus baseline *P < 0.05, †P < 0.01,‡P < 0.001, §P < 0.0001 by Dunnett test, ¶P < 0.05 by paired t test.


in total UPDRS score was reported in the selegiline-treated groupin the prior phase III trial (6.26-point reduction at week 12),14 andwith 600 mg levodopa in the ELLDOPA study (6-point reductionat week 24) in patients with early PD.18 Disease severity at base-line was evaluated according to the modified H/Y staging in these

FIGURE 7. Mean changes in the total UPDRS scores from baseline in theIII–selegiline, n = 68. Therewere significant differences in changes frombathe phase III–selegiline and phase III–placebo groups: *P < 0.05, at week 0washout periods were 18.51 ± 10.65 (phase III–selegiline) and 18.89 ± 9



studies and was comparable to the mean modified H/Y stage atbaseline in the present study.14,18 This result suggests that thereare sufficient remaining dopaminergic neurons in selegiline-treated patients with early PD to induce vigorous dopaminergic ac-tivation compared with patients with advanced PD via MAO-B

phase III and long-term study. Phase III–placebo, n = 63; phaseseline in total UPDRS score at week 12 of the phase III trial betweenof the long-term study; †P < 0.01 (analysis of covariance). Themean.30 (phase III–placebo). Data are expressed as mean ± SD.




TABLE 3. Common ADRs With an Incidence of ≥2%

Patients Evaluated: n = 131

≥2% ADRs

No. %

Total 58 44.3Gastrointestinal disordersConstipation 6 4.6Vomiting 3 2.3

General disorders and administration site conditionsFall 3 2.3

Blood examination resultsBlood creatine phosphokinase increased 5 3.8White blood cell count decreased 3 2.3

Musculoskeletal and connective tissue disordersBack pain 4 3.1

Nervous system diseaseSomnolence 3 2.3

Psychiatric disordersInsomnia 7 5.3

Vascular disordersHypertension 4 3.1Orthostatic hypotension 3 2.3


inhibition, leading to an improvement of motor functions. This in-terpretation is supported by the PD MED pragmatically random-ized trial in patients with early PD, which suggests that MAO-Binhibitors are as effective as dopamine agonists, based on Parkinson’sdisease Questionnaire-39 evaluation.19 Together, our results haveshown that selegiline monotherapy is an effective treatment optionfor patients with early PD.

In the present study, we observed a significant improvementin total UPDRS score (Fig. 3A) and 4 major motor symptoms(Fig. 6) at week 4, and further improvements from week 4 to 8.Notably, a similar improvement pattern was observed in thephase III trial with the same parameters. These results clearlyindicate that treatment with selegiline produces a dose-dependent improvement in a total UPDRS score. We applieda “forced titration” design in this study; therefore, it remainsunclear whether the long-term administration of smaller dosesof selegiline is less effective, as measured by total UPDRS score.

The incidence rates of ADRs associated with selegiline treat-ment did not increase during administration of 10 mg selegiline inthis study (weeks 9–56; Table 3), indicating that the ADRs werenot influenced by medication duration. In the present study, themost common ADRs were insomnia (5.3%, 7/131), constipation(4.6%, 6/131), increases in blood creatine kinase (3.8%, 5/131),

TABLE 4. Incidence of AEs and ADRs During Different Periods

TimeDay 1–Week 8

(n = 131)

Weeks9–16

(n = 127)

W1

(n

Type of events AE ADR AE ADR AE

No. AEs or ADRs* 67 35 41 15 39No. patients with AEs or ADRs* 46 26 30 10 32Incidence rate, % 35.1 19.8 23.6 7.9 27.1

*Not duplicate.



back pain (3.1%, 4/131), hypertension (3.1%, 4/131), vomiting(2.3%, 3/131), falls (2.3%, 3/131), decreases in white blood cellcounts(2.3%, 3/131), somnolence (2.3%, 3/131), orthostatic hy-potension (2.3%, 3/131), dizziness (1.5%, 2/131), nausea (1.5%,2/131), dry mouth (1.5%, 2/131), headache (none/131), fatigue(none/131), and anxiety (none/131). The deprenyl and tocopherolantioxidative therapy of parkinsonism study8 revealed selegiline-associated ADRs (≥2%; median administration period, 719 days)were elevated alanine aminotransferase (7.8%, 31/399), musculo-skeletal injury (7.3%, 29/399), elevated aspartate aminotransfer-ase (7.0%, 28/399), nausea (2.0%, 8/399), and cardiacarrhythmia (2.0%, 8/399). Pålhagen et al10 reported that the mostcommon ADRs associated with selegiline treatment (medianadministration period, 12.7 months) were gastrointestinal ad-verse reactions (dry mouth, cholecystitis, flatulence, gastroin-testinal discomfort, nausea, and diarrhea; 14.8%, 12/81). Data20

from long-term double-blind studies using selegiline monother-apy in patients with early PD from Europe and the UnitedStates10–13 reported the most common ADRs were insomnia(10.9%, 20/183), dizziness (9.3%, 17/183), nausea (6.0%, 11/183), headache (5.5%, 10/183), fatigue (1.6%, 3/183), dry mouth(1.6%, 3/183), and anxiety (0.5%, 1/183). The incidence rates ofADRs in the selegiline group were not significantly different fromthose of the placebo group; however, the reason underlying thedifferences in ADR profiles between studies has not been eluci-dated. Nonetheless, individual ADR incidence rates in our studywere relatively low and similar to other studies,8,10–13,20 including1 study20 that reported accumulated ADRs and suggested positivetolerability of selegiline. Consequently, the long-term monother-apy of selegiline for early PD is reported as safe in the US and Eu-ropean studies. In line with this, we consider that 10 mg selegilineis well tolerated for long-term use in Japanese patients withearly PD.

Post hoc integrative analyses of the phase III trial data and thepresent study revealed that the phase III–selegiline group had asignificantly lower total UPDRS score compared with the phaseIII–placebo group (P = 0.0006) at the end of the drug washout pe-riod (median, 15 days). This indicated that selegiline may havesustained efficacy in patients with early PD. We speculated thatthis might be due to neuronal plasticity and as its symptomatic ef-fects associated with dopamine augmentation via MAO-B inhibi-tion. The differences in score between groups at the end of thedrug washout period gradually reduced and then disappeared;however, post hoc analysis showed sustained symptomatic ef-fects of selegiline, but we could not determine any disease-modifying21–23 or neuroprotective effects. Therefore, additionallong-term, double-blind studies are required to clarify the disease-modifying effect of selegiline.

The limitation of this study resides in its open-label studydesign, which does not include a parallel, randomized, control

eeks7–24= 118)

Weeks25–32

(n = 109)

Weeks33–40(n = 97)

Weeks41–48(n = 94)

Weeks49–56(n = 91)

ADR AE ADR AE ADR AE ADR AE ADR

26 38 15 30 10 28 13 20 1322 30 13 24 10 24 11 14 1018.6 27.5 11.9 24.7 10.3 25.5 11.7 15.4 11.0





arm. Nonetheless, we consider this study is important, as itshowed the long-term safety of selegiline monotherapy inJapanese patients.

In conclusion, this study demonstrated that selegilinemonotherapy was well tolerated and produced sustained symp-tomatic improvements in Japanese patients with early PD in this52-week study.

ACKNOWLEDGMENTSWe thank the following additional individuals who partici-

pated in the study as investigators:Kazunori Itoh, Sanae Honma, Masahiko Tomiyama, Tetsuya

Maeda, Takashi Abe, Takafumi Hasegawa, Hiroyuki Enomoto,Takao Hashimoto, Mitsuya Morita, Kyoichi Nomura, HidekiShimura, Fusako Yokochi, Masahiko Suzuki, Shin-ichiro Kubo,Hidehiro Mizusawa, Hideki Takubo, Satoshi Orimo, KazukoHasegawa, Ichiro Imafuku, Hitoshi Yamada, Noriko Kawashima,Tsuyoshi Uchiyama, Tetsushi Atsumi, Masahisa Katsuno, KotaroTanaka, Hideyuki Sawada, Takahiko Tokuda, Yoshihisa Tatsuoka,Sadayuki Matsumoto, Yoshiyuki Mitsui, Yasuhiro Hiwatani,Ken-ichi Kashihara, Yoshito Nagano, Junji Yoshinaga, YoshihikoNishida, Yasushi Osaki, Noriko Nishikawa, Yoshio Tsuboi, andAkira Sato.

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