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Keywords:

  • rasagiline;
  • Parkinson's disease;
  • treatment;
  • dopamine agonists;
  • ropinirole;
  • pramipexole

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References

Dopamine agonists (DA) are often used as first-line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase-B (MAO-B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18-week, randomized, double-blind, placebo-controlled trial of rasagiline 1 mg/d as an add-on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent-to-treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, −2.4 ± 0.95; 95% confidence interval [CI], −4.3, −0.5; P = 0.012). Mean improvement (LS mean ± SE) was −3.6 ± 0.68 in the rasagiline group and −1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society

Dopamine agonists (DAs) are often used as first-line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years,[1, 2] at which time the DA dosage must be increased or other antiparkinsonian medications added. This can be problematic in that higher dosages of DAs are associated with a higher risk of adverse events (AEs) such as impulse control disorders (ICDs), excessive daytime sleepiness, sudden-onset sleep, edema, and hallucinations.[3-5] Levodopa (l-dopa) is also often introduced at this stage but is associated with the development of motor complications (which is often the very reason that PD therapy was started with a DA, especially in younger subjects). Indeed, because the risk of motor complications is closely linked to the time of initiation of l-dopa and total duration of exposure,[6, 7] one may choose to continue to use l-dopa–sparing strategies to further delay the need for l-dopa, as long as adequate control can be maintained with other medications.

Rasagiline acts by reducing striatal dopamine metabolism,[8] and this mode of action provides a rationale for add-on therapy to DAs, to provide additional symptomatic benefit while potentially maintaining good tolerability and further delaying the initiation of l-dopa therapy. However, prospective data examining the effect of rasagiline when added to DA monotherapy (i.e., in the absence of l-dopa) are lacking. The aim of this study was therefore to determine the clinical efficacy, safety, and tolerability of once-daily rasagiline as an add-on therapy for subjects with early PD who are not optimally controlled on DA monotherapy.

Patients and Methods

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References

This was an 18-week, randomized, double-blind, placebo-controlled trial of rasagiline 1 mg/d as an add-on to DA therapy in early PD subjects not adequately controlled on their current treatment regimen. The study was conducted from December 2009 through October 2012 at 69 centers in the United States. It was conducted in accordance with Good Clinical Practice guidelines, was approved by appropriate institutional review boards, and all subjects provided written informed consent to participate. The study is registered with ClinicalTrials.gov, number NCT01049984.

Participants

Key inclusion criteria were diagnosis of PD (at least 2 of 3 cardinal signs—resting tremor, bradykinesia, rigidity—and no other known or suspected cause of parkinsonism), age 30 years or older, and Hoehn-Yahr stage from 1 to 3 (on treatment). Eligible subjects were those who were on a stable dosage of a dopamine agonist (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) and whose symptoms were not optimally controlled. Dopamine agonist therapy was required to be ongoing for 30 days or more but could not have been ongoing for more than 5 years preceding baseline. Concomitant therapy with amantadine and anticholinergics at stable dosages was permitted. Key exclusion criteria were prior L-dopa treatment for more than 21 consecutive days or within 90 days before baseline, moderate or severe motor fluctuations, mini-mental state examination score less than 26, Beck Depression Score greater than 14, ICD, uncontrolled hypertension, clinically significant hepatic impairment, and pregnancy or lactation. Concomitant monoamine oxidase (MAO) inhibitors (within 60 days before baseline) and medications contraindicated for use with rasagiline were not permitted. Concomitant antidepressant use was at the discretion of the investigator.

Study Design

Subjects underwent screening and baseline assessments at visit 1, and those who met eligibility criteria were randomized 1:1 to the addition of rasagiline 1 mg/d or matching placebo using blocks stratified by center. Site personnel, subjects, and sponsor were blinded to treatment assignment. Subsequent study visits were undertaken at weeks 9 (visit 2) and 18 (visit 3). Dosages of PD medications, including dopamine agonists and any others (anticholinergics and amantadine) were unchanged throughout the course of the study. Rescue treatment with L-dopa was permitted, if required, once the subject had started treatment with study drug and had completed 30 days of treatment. If rescue L-dopa therapy was required, an end-of-study assessment was performed before its initiation.

Study Medications

Teva Pharmaceutical Industries, Limited (Kfar Saba, Israel) manufactured rasagiline 1-mg tablets and matching placebo. Catalent Pharma Solutions (Somerset, NJ, USA) packaged, labeled, and shipped study medication.

Outcome Measures

Unified Parkinson Disease Rating Scale (UPDRS) scoring,[9] parts I, II, III, and the Brief Smell Identification Test (B-SIT)[10] were performed at baseline, week 9, and week 18. The Scales for Outcomes in PD-cognition (SCOPA-cognition)[11] and the 39-item PD Questionnaire (PDQ-39)[12] were performed at baseline and week 18. The Patient Global Impression of Improvement (PGI-I) and the Clinician Global Impression of Improvement (CGI-I)[13] were performed at week 18.

Treatment-emergent AEs were recorded throughout the study. Electrocardiogram and blood laboratory tests were obtained at screening only. Blood pressure and pulse were recorded at screening and weeks 9 and 18. The SCOPA daytime sleepiness score[14] was obtained at baseline, week 9, and week 18.

Statistical Analyses

The primary efficacy variable was the change in total UPDRS score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The primary efficacy analysis was performed using the modified intent-to-treat (mITT) population (defined as all randomized subjects who took at least one dose of study medication and who had both a baseline and at least one post-baseline efficacy assessment) and used a repeated-measures model with week in study, week in study by treatment interaction, and pooled center included as fixed effects and baseline total UPDRS score included as a covariate. Safety outcomes were assessed using the safety population, which included all subjects who took at least one dose of study drug.

Secondary efficacy outcomes included change from baseline to week 18 in UPDRS Part III (motor examination) and UPDRS Part II (activities of daily living) scores, which were analyzed in the same way as the primary outcome variable. Additional secondary efficacy outcome variables included PGI-I, CGI-I, and CGI-S at week 18. The Cochran-Mantel-Haenzel test was used to compare the distribution of subjects between groups, with treatment and pooled center as strata for PGI-I and CGI-I, and with treatment, pooled center, and baseline measurement as strata for CGI.

Exploratory efficacy analyses included evaluation of change from baseline to week 18 in each of the four UPDRS motor subscores (bradykinesia items 23–26, 31; tremor items 16, 20, 21; rigidity item 22; postural instability/gait items 13–15, 29, 30) using the Wilcoxon rank sum test. Change in PDQ-39 single index score and its eight dimension scores, SCOPA-cognition, and B-SIT were also evaluated as exploratory outcomes using a repeated-measures model.

No P value adjustments were made for multiplicity of secondary and exploratory analyses.

Determination of Sample Size

A total of 140 evaluable subjects in each arm was calculated to provide 80% power to detect a minimum difference of 3 points in Total UPDRS score at the 5% significance level, assuming a standard deviation of 9.

Role of the Funding Source

The study was funded by Teva Neuroscience and H. Lundbeck A/S and conducted by Teva Neuroscience. Data collection was coordinated by Teva Neuroscience and designates, who also contributed to the study's conduct. Teva Pharmaceutical Industries supported reporting of study results by procuring medical writing support and as an employer of two of the manuscript's authors. All authors had full access to all data, contributed to manuscript revisions, and had final approval for submission. Robert A. Hauser, MD, wrote the initial draft and had final responsibility for the decision to submit the paper for publication.

Results

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References

Subject Disposition

Three hundred twenty-eight subjects were enrolled and randomized in the study (Fig. 1). Two subjects (one from each group) were enrolled and randomized but not dosed and are therefore not part of the Safety (defined as having taken at least one dose of study medication) or mITT populations. Three hundred twenty-six subjects (99.4%) constituted the Safety population, 321 (97.9%) constituted the mITT, and 289 (88.1%) completed the study.

image

Figure 1. Subject disposition.

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Demographics, Baseline Characteristics, and Concomitant Medications

Subject demographics and baseline PD characteristics of the mITT population are presented in Table 1. Mean age ± SD was 62.6 ± 9.7 years, and 220 (67.5%) were male. The mean duration of PD was 2.1 ± 2.1 years, and mean Total UPDRS score was 31.0 ± 13.83; 133 (41.4%) subjects were taking ropinirole, including 50 on ropinirole IR and 83 on ropinirole XL, and 188 (58.6%) were taking pramipexole, including 154 on pramipexole IR and 34 on pramipexole ER. Mean ± SD daily ropinirole dosage at baseline was 8.0 ± 4.8 mg/d, and mean daily pramipexole dosage was 1.5 ± 0.9 mg/d. Twenty-two subjects (6.7%) (rasagiline, n = 12 [7.2%]; placebo, n = 10 [6.1%]) were receiving concomitant amantadine, and 12 subjects (3.7%) (rasagiline, n = 7 [4.3%]; placebo, n = 5 [3.2%]) were receiving concomitant anticholinergic medication.

Table 1. Demographics and baseline disease characteristics (mITT population)
ParameterRasagiline (N = 159)Placebo (N = 162)
  1. Abbreviations: PD, Parkinson's disease; UPDRS, Unified Parkinson Disease Rating Scale; SD, standard deviation; AE, adverse event.

Male sex; n (%)108 (67.9%)111 (68.5%)
Age; years mean ± SD62.3 ± 9.362.8 ± 10.1
Duration of PD; years mean ± SD2.2 ± 2.22.1 ± 1.9
Total-UPDRS score; mean ± SD(N = 158 for both groups)32.1 ± 14.429.8 ± 13.2
UPDRS Part III (motor) score; mean ± SD(N = 159 for both groups)22.2 ± 10.720.4 ± 10.0
Pramipexole; n(%)Dose; mg/day mean ± SD96 (60.4%)1.5 ± 0.992 (56.8%)1.5 ± 0.9
Ropinirole; n(%)Dose; mg/day mean ± SD63 (39.6%)7.1 ± 4.770 (43.2%)8.9 ± 4.8
Reason for study entry
Suboptimal control without dose limiting AEs; n(%)7859
Duration of dopamine agonist therapy; days mean ± SD411.2 ± 430.6380.2 ± 359.1
Pramipexole dose; mg/day mean ± SD2.4 ± 1.12.4 ± 1.0
Ropinirole dose; mg/day mean ± SD12.3 ± 6.410.6 ± 6.0
Dose limiting AEs; n10084
Duration of dopamine agonist therapy; days mean ± SD407.5 ± 397.5375.1 ± 362.1
Pramipexole dose; mg/day mean ± SD2.6 ± 1.42.0 ± 0.9
Ropinirole dose; mg/day mean ± SD9.9 ± 4.48.5 ± 4.4

Of the mITT population, 137 subjects (42.7%) were judged not optimally controlled on DA therapy at study entry and did not report a history of dosage-limiting AEs, and 184 (57.3%) subjects were judged not optimally controlled on DA therapy and reported a history of or were observed to experience a dosage-limiting AE before study entry (Table 1).

There were no significant differences between groups in the proportion of subjects who required rescue l-dopa treatment (rasagiline, n = 6 [3.8%]; placebo, n = 5 [3.1%]), or in the time to initiation of rescue therapy.

Efficacy

The study met its primary endpoint. Results demonstrated a significantly greater improvement in Total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, −2.4 ± 0.95; 95% confidence interval [CI], −4.3, −0.5; P = 0.012) (Table 2). Patients in the rasagiline group improved from a mean ± SD baseline score of 32.1 ± 14.37 to 28.1 ± 14.35 at week 18 (LS mean ± SE treatment effect, −3.6 ± 0.68). Patients in the placebo group improved from a baseline of 29.8 ± 13.22 to 28.9 ± 14.53 at week 18 (treatment effect, −1.2 ± 0.68) (Fig. 2).

Table 2. Efficacy results
 Rasagiline (N = 159)Placebo (N = 162)P Value Treatment Effect (Rasagiline–Placebo)
  1. No P value adjustments were made for multiplicity of secondary and exploratory analyses.

  2. Abbreviations: UPDRS, Unified Parkinson Disease Rating Scale; SD, standard deviation, SE, standard error; LS, least squares; CI, confidence interval; ADL, activities of daily living; CGI, Clinician Global Impression of Improvement.

UPDRS total score   
Baseline; mean ± SD32.1 ± 14.429.8 ± 13.20.012
Week 18; mean ± SD28.1 ± 14.428.9 ± 14.5 
Treatment effect; LS mean ± SE−3.6 ± 0.7−1.2 ± 0.7 
(95%CI)(−0.5, −2.2)(−2.5, 0.2) 
UPDRS Part II (ADL) score   
Baseline; mean ± SD8.6 ± 4.47.9 ± 4.40.3
Week 18; mean ± SD8.3 ± 4.88.3 ± 5.11 
Treatment effect; LS mean ± SE−0.1 ± 0.30.3 ± 0.3 
(95%CI)(−0.6, 0.5)(−0.2, 0.9) 
UPDRS Part III (motor) score   
Baseline; mean ± SD22.2 ±10.720.4 ± 10.00.007
Week 18; mean ± SD18.4 ± 10.519.1 ± 10.2 
Treatment effect; LS mean ± SE−3.4 ± 0.5−1.6 ± 0.5 
(95%CI)(−4.4, −2.5)(−2.5, 0.7) 
Site rated CGI at week 18; n (%)  0.255
Not assessed-1 (0.6) 
Very much improved5 (3.1)5 (3.1) 
Much improved21 (13.2)20 (12.3) 
Minimally improved45 (28.3)39 (24.1) 
No change63 (39.6)53 (32.7) 
Minimally worse21 (13.2)42 (25.9) 
Much worse3 (1.9)1 (0.6) 
Very much worse1 (0.6)1 (0.6) 
Subject rated CGI at week 18; n (%)  0.996
Not assessed-1 (0.6) 
Very much improved7 (4.4)7 (4.3) 
Much improved18 (11.3)18 (11.1) 
Minimally improved39 (24.5)40 (24.7) 
No change52 (32.7)52 (32.1) 
Minimally worse36 (22.6)35 (21.6) 
Much worse5 (3.1)8 (4.9) 
Very much worse2 (1.3)1 (0.6) 
image

Figure 2. Change in least squares (LS) mean ± SE total UPDRS. Repeated-measures analysis of covariance model.

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Secondary efficacy results are summarized in Table 2. UPDRS Part III (motor) scores were also significantly more improved in the rasagiline group than the placebo group (LS mean difference ± SE, −1.8 ± 0.67; 95%CI, −3.1, −0.5; P = 0.007). However, UPDRS Part II (activities of daily living [ADL]) scores were not significantly different across groups (LS mean difference ± SE, −0.4 ± 0.37; 95%CI, −1.1, 0.3; P = 0.301). In addition, no significant differences were noted for PGI-I, CGI-I, or CGI-S at week 18.

Exploratory analyses identified significantly greater improvements in the rasagiline compared with the placebo group in UPDRS motor subscales for bradykinesia (P = 0.002), tremor (P = 0.005), and postural instability/gait (P = 0.031), but not rigidity (P = 0.222). Mean ± SD baseline B-SIT scores were 6.1 ± 2.4 and 6.0 ± 2.5 for the rasagiline and placebo groups and remained unchanged in both groups at week 18 (mean change from baseline, −0.1 ± 2.2 and −0.0 ± 1.9, respectively). Likewise, no significant differences in change in SCOPA-cognition or PDQ-39 scores were observed across groups.

Safety and Tolerability

Treatment emergent AEs are summarized in Table 3. Overall, 19 (11.7%) subjects in each group discontinued the study. Thirteen (8.0%) subjects in the rasagiline group discontinued the study because of AEs, compared with seven (4.2%) in the placebo group. Nausea led to discontinuation in three patients (n = 2 in the rasagiline group and n = 1 in the placebo group), dizziness led to discontinuation in two patients (both in the rasagiline group), and all other AEs leading to discontinuation each occurred in one subject. One hundred four subjects (64.2%) in the rasagiline group reported an AE compared with 100 subjects (61.0%) in the placebo group. Most AEs in both groups were mild or moderate.

Table 3. Summary of Treatment-Emergent AEs
n(%)Rasagiline (N = 162)Placebo (N = 164)
  1. Abbreviation: AE, adverse event.

Subjects with an AE104 (64.2)100 (61.0)
Subjects with a serious AE8 (4.9)5 (3.0)
Subjects with an AE leading to discontinuation13 (8.0)7 (4.3)
AEs Occurring in ≥5% of Either Group
Dizziness12 (7.4)10 (6.1)
Peripheral edema12 (7.4)7 (4.3)
Somnolence11 (6.8)11 (6.7)
Nausea10 (6.2)7 (4.3)
Headache10 (6.2)7 (4.3)
Fall9 (5.6)2 (1.2)
Tremor7 (4.3)10 (6.1)

The most common AEs overall (rasagiline vs. placebo) were dizziness (12 [7.4%] vs. 10 [6.1%]), somnolence (11 [6.8%] vs. 11 [6.7%]), and headache (10 [6.2%] vs. 7 [4.3%]). No significant differences were observed in change in SCOPA daytime sleepiness from baseline to week 18.

No subjects died during the study. A total of 13 subjects (4.0%) reported 16 serious adverse events (SAEs) during the study (Table 4). In the rasagiline group, eight (4.9%) subjects reported nine SAEs, and in the placebo group, five (3.0%) subjects reported seven SAEs. None of the SAEs was considered related to study medication by the investigator, and all resolved. One subject in the rasagiline group experienced an SAE of presyncope.

Table 4. Summary of serious treatment-emergent AEs
 SeverityStudy drug action
Rasagiline
PresyncopeSevereDrug withdrawn
SyncopeSevereDrug interrupted
Humerus fractureSevereDrug withdrawn
Intervertebral discdisorderoperationMildSevereNoneNone
Acute cholecystitisSevereDrug withdrawn
Ankle fractureSevereNone
Lumbar spine stenosisSevereDrug interrupted
SpondylolisthesisModerateDrug interrupted
Placebo
DyspneaSevereDrug withdrawn
CholelithiasisMildNone
Parkinson's diseaseSevereDrug withdrawn
Myocardial ischemiaSevereNone
HematuriaModerateNone
Urinary retentionModerateNone
Fractured sacrumSevereNone

Discussion

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References

In this prospective, randomized, double-blind trial, rasagiline 1 mg/d provided significant improvements in UPDRS total and motor scores when added to DA therapy. The addition of rasagiline was well tolerated, and there were no clinically relevant increases in AEs typically associated with dopamine agonists, including sleepiness, sudden-onset sleep, confusion, hallucinations, orthostatic hypotension, or ICDs. Thus, improvements were achieved without compromising tolerability.

Although efficacy results were statistically significant, interpretation of clinical relevance is more complicated. Changes in UPDRS ADL scores were not significantly different across groups, suggesting that the observed difference in change in Total UPDRS scores was mostly driven by motor improvements.

Several analyses have been performed to determine the minimal clinically relevant difference (MCRD) on the UPDRS, with results ranging between 3 and 8 for Total UPDRS scores and between 1.5 and 3 for UPDRS motor scores.[15-18] This wide range of results likely reflects differences in the methodologies used to estimate MCRD (including study population, treatment, double-blind controlled, open-label or observational, period evaluated, and so forth), and therefore there may not be a single identifiable MCRD value but rather a range of values.[17] Our result of a difference in UPDRS motor scores of 1.8 points appears to be in the suggested clinically relevant range. In contrast, our result of a difference in total UPDRS scores of 2.4 points appears to be below the suggested minimal clinically relevant range. Lack of difference in PGI-I and PDQ-39 scores across groups is consistent with this finding.

The magnitude of UPDRS benefit we observed for rasagiline as an add-on to DA therapy versus placebo appears smaller than what was observed in pivotal trials of rasagiline as monotherapy or as an add-on to l-dopa in later disease, which have all been above the MCRD.[17] One potential reason for this result is that subjects enrolled in our study could have been doing well enough that a ceiling effect prevented a more robust difference from being observed. However, this possibility appears unlikely in that baseline Total UPDRS scores in this study were higher than those in the TEMPO monotherapy trial (baseline Total UPDRS, ≈ 25).[19] It is also possible that the study duration of 18 weeks was too short to see a larger effect (vs. the average 26-week duration of the pivotal trials).

We also must consider potential pharmacological reasons for a smaller treatment effect. The mechanism of symptomatic benefit of MAO-B inhibitors is considered to be increased dopamine concentration in the synapse attributable to reduced dopamine clearance. Because subjects on DA monotherapy have more advanced disease than subjects who are treatment naïve, one might expect them to have a greater reduction in endogenous dopamine production, thereby reducing the potential benefit of an MAO-B inhibitor. In addition, treatment with a DA may activate dopamine autoreceptors to further reduce endogenous dopamine release.[20, 21] Even if the MAO-B inhibitor is able to boost synaptic endogenous dopamine concentration, competition for postsynaptic receptors attributable to occupancy of those receptors by the DA may blunt the clinical effect. Moreover, both ropinirole and pramipexole have a higher relative affinity for D3 receptors than dopamine itself,[22] and their presence might blunt the D3 receptor activation boost from MAO-B inhibition, possibly minimizing neuropsychiatric benefits and subject self-perception of improvement. Thus, multiple pharmacologic reasons might explain the magnitude of clinical effect observed in this DA-treated population. Once L-dopa is added, and L-dopa-derived dopamine production augments dopamine concentration in the synapse, a greater response to the addition of an MAO-B inhibitor might be expected. Indeed, in more advanced disease, when subjects are experiencing motor fluctuations on l-dopa, the addition of rasagiline significantly improves UPDRS motor and ADL scores.[23, 24] In this population, no difference in the clinical benefits of rasagiline has been observed in subjects who are on a DA compared with those who are not.[25]

The current study included olfaction as an exploratory variable because rasagiline was demonstrated to ameliorate olfactory deficits in an alpha-synuclein mouse model of PD (although improvements in olfactory bulb neurogenesis were not identified)[26] and was associated with significant improvement in olfaction in PD patients in an open-label study.[27] However, a recent double-blind, placebo-controlled study reported no significant olfactory improvements with rasagiline,[28] and our results were also negative.

Our study has several important limitations. Subjects with a history of an ICD on a DA were excluded, so it does not address whether rasagiline can be added to a lower dosage of the DA to avoid reemergence of the ICD. In addition, the study only enrolled patients on pramipexole and ropinirole. This study was designed to evaluate the short-term efficacy and safety of adding rasagiline to DA therapy. It did not compare adding rasagiline to other treatment strategies such as increasing the DA dosage, nor did it evaluate the long-term ability of rasagiline to provide an l-dopa–sparing effect.

In conclusion, the addition of once-daily rasagiline 1 mg/d significantly improved UPDRS-total and motor scores in subjects suboptimally controlled on DA monotherapy and was well tolerated. No clinically relevant increases in AEs typically associated with dopamine agonists occurred. Rasagiline has demonstrated efficacy as a monotherapy, as an adjunct to DAs, and as an adjunct to l-dopa in patients experiencing motor fluctuations.

Author Roles

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

RAH: 1A, 2C, 3A, 3B

DS: 1A, 2C, 3B

AC: 1A, 1B, 1C, 2C, 3B

EE: 1A, 2A, 2B, 3B

SI: 1A, 2C, 3B

Financial Disclosures

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References

Dr. Hauser has received honoraria or payments for consulting, advisory services, or speaking services over the past 12 months from AbbVie, Allergan, AstraZeneca, Biotie Therapeutics, Ceregene, Chelsea Therapeutics, Cleveland Clinic, Eli Lilly, GE Healthcare, Impax Laboratories, Neurocrine, Indus, Ipsen Biopharmaceuticals, Lundbeck, Merck/MSD, Noven Pharmaceuticals, Pfizer, Straken Pharmaceuticals, Targacept, Teva Pharmaceuticals Industries, Ltd., Teva Neuroscience, Upsher-Smith Laboratories, UCB, UCB Pharma SA, University of Houston, US World Meds, Xenoport, Zambon Company SpA. Dr. Hauser's institution has received research support over the past 12 months from Abbot Laboratories, Addex Therapeutics, Allergan, AstraZeneca, Biotie Therapeutics, Chelsea Therapeutics, Civitas, GE Healthcare, Impax Laboratories, Ipsen Biopharmaceuticals, Merck/MSD, Merz, Michael J. Fox Foundation for Parkinson's Research, NINDS, Parkinson Study Group, Schering-Plough, Teva Neuroscience, UCB, Vita-Pharm.Dr. Hauser has received royalties in the last 12 months from the University of South Florida.

Dr. Isaacson has received honoraria or payments for consulting, advisory services, speaking services, research grants over the past 12 months from AbbVie, Acadia, Adamas, Addex, Allergan, AstraZeneca, Avanir, Biotie, Brittania, Chelsea Therapeutics, Civitas, Eisai, Genus, GE Healthcare, GSK, Impax, Ipsen, Lilly, Lundbeck, Kyowa, Merck/MSD, Merz, Michael J. Fox Foundation for Parkinson's Research, Purdue, Roche, Schering-Plough, Shire, Serono, Teva Neuroscience, UCB Pharma, US World Meds, XenoPort.

Dr. Silver has received honoraria or payments for advisory and speaking services over the past 12 months from Accera Pharma, Boehringer-Ingelheim, Glaxo Smithkline, Novartis Pharmaceuticals, Johnson and Johnson, Kyowa Pharmaceuticals, Ipsen, Pfizer, Forrest Pharmaceuticals, Merz Pharma, Innovex Pharmaceuticals, Teva Neuroscience, UCB Biosciences. Drs. Hauser, Isaacson, and Silver have received consulting fees for attending ANDANTE steering committee meetings. They have not received any payments for the preparation of this manuscript. Drs. Choudhry and Eyal are employed by Teva Pharmaceuticals.

This study was funded by Teva Neuroscience and H. Lundbeck A/S.

Acknowledgments

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References

We thank the ANDANTE investigators, Elijahu Berkovich (Teva Pharmaceutical Industries) and also Anita Chadha-Patel (ACP Clinical Communications Ltd. funded by Teva Pharmaceutical Industries) for medical writing support (literature searching, referencing and editing) in the development of this report.

References

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Author Roles
  7. Financial Disclosures
  8. Acknowledgments
  9. References