This page contains a Flash digital edition of a book.
Activities of Daily Living Subscale for Early Parkinson’s Disease


only the ADL subscale showed a significant difference between the early- and delayed-start groups (see Figure 2). By that time, all patients had been receiving the same drug for at least nine months and, therefore, any difference between the two groups at this stage was likely to indicate only the disease-modifying effects of the drug. At week 36, the contribution of the motor subscale was approximately twice that of the ADL subscale (64 and 29 %, respectively, with rasagiline 1 mg/day). However, at week 72, the contribution of the ADL subscale to treatment effect had increased to 41 %, whereas the motor component had decreased to 51 %. Furthermore, the ADL subscale was the only one to show a statistically significant between-group difference (early- versus delayed-start rasagiline 1 mg/day).


The ADAGIO cohort (i.e., patients with early, very mild PD) showed a low rate of progression on the UPDRS, an effect previously observed in the Neuroprotection exploratory trials in PD (NET-PD) study. Analysis of data from the ADAGIO trial using the UPDRS-ADL subscale supports the notion that it may be a more appropriate measure to assess disease progression than the UPDRS motor subscale.57,58


Use of Additional Antiparkinsonian Medication in the Attenuation of Disease Progression with Azilect Given Once Daily Trial


During the placebo-controlled phase of the ADAGIO trial, it was also shown that significantly fewer patients receiving rasagiline required additional antiparkinsonian medication (levodopa or dopamine agonists) compared with those receiving placebo (9, 9, and 18 % with rasagiline 1 and 2 mg/day and placebo, respectively; odds ratios 0.41 [95 % CI 0.25–0.65] p=0.0002 for rasagiline 1 mg/day versus placebo and 0.41 [95 % CI 0.26–0.64] p=0.0001 for rasagiline 2 mg/day versus placebo), indicating that the probability of requiring additional antiparkinsonian medication was approximately 60 % lower in the early-start groups than in the pooled placebo group.31


The percentages of patients who needed


additional antiparkinsonian medication and the time to receiving that medication are given in Figure 3.


Assessment of Fatigue in the Attenuation of Disease Progression with Azilect Given Once Daily Trial


Fatigue is a common and consistent problem in PD and often pre-dates the onset of motor symptoms,59


(PFS) another useful tool in assessing PD.60


which makes the Parkinson Fatigue Scale The ADAGIO trial assessment


using the PFS showed that rasagiline 1 mg/day was beneficial on fatigue. Patients in the placebo groups had a significantly greater worsening in PFS scores from baseline to the last observed value than patients in the groups receiving rasagiline 1 mg/day (treatment difference -0.14 [standard error; SE 0.05]; p=0.0032) and 2 mg/day (treatment difference -0.19 [SE 0.05]; p<0.0001).31


Other Delayed-start Trials


To date, few trials have employed delayed-start methodology and have assessed ADL as a measure of disease progression in PD. The previous rasagiline trial TEMPO demonstrated that, during its placebo-controlled, double-blind six month phase (Phase 1), rasagiline was safe and efficacious compared with placebo for


US NEUROLOGY patients with early PD.40 At baseline, patients enrolled in the TEMPO


trial had a significantly higher mean total UPDRS score than those enrolled in the ADAGIO trial (24.5−25.9 versus 20.4, respectively).40,52 From month seven to month 12 of the TEMPO trial, early- and delayed-start rasagiline treatment were compared: in patients who received rasagiline 1 mg/day treatment for 12 months (early-start treatment), the functional decline was less pronounced than in patients who received placebo for six months followed by rasagiline for six months (delayed-start treatment).40,61


After 52 weeks, the mean


changes in total UPDRS scores from baseline for the three different treatment groups were: +3.01 (with rasagiline 1 mg/day), +1.97 (with rasagiline 2 mg/day), and +4.17 (with delayed-start rasagiline 2 mg/day). During the entire 6.5-year follow-up period, this change was 2.5 units (or 16 %) in favor of the early-start versus delayed-start rasagiline group. However, it is difficult, from these results, to draw firm conclusions regarding the disease-modifying effect of rasagiline due to the high drop-out rate of patients during the extension study.62


In the TEMPO trial, rasagiline 1 and 2 mg/day (early-start rasagiline) were both superior to delayed-start rasagiline in terms of changes in UPDRS scores in patients who had high UPDRS scores at baseline.61


Similar results


were observed in the ADAGIO trial patients with the highest quartile of UPDRS scores, suggesting that the effect of rasagiline 2 mg/day on symptoms may have masked a benefit in terms of functional decline with early-start treatment in patients with very mild disease.52


During its


comparison phase (month seven to month 12), the TEMPO study showed a mean difference of 39.1 % in ADL subscore changes from baseline, and a mean difference of 11.9 % in motor subscore changes from baseline, between the early-start and delayed-start rasagiline groups;62 this supports the concept that on-motor symptoms assessed by the ADL subscale may be more stable markers of disease progression.56 The UPDRS in its entirety may be less sensitive to changes in early PD and may not capture improvements in non-motor areas.63–65 Improvements of ADL subscores in rasagiline-treated patients are consistent with significant benefits in non-motor symptoms compared with placebo.66


A delayed-start design also was used to assess a potential disease-modifying effect of the dopamine agonist pramipexole. The Pramipexole on underlying disease (PROUD) study enrolled approximately 500 patients with early PD. During Phase 1, patients received 1.5 mg/day pramipexole or placebo for 6−9 months. During Phase 2 (i.e, until study end at month 15), those receiving placebo during Phase 1 received pramipexole. The primary endpoint was the change in total UPDRS score (sections 1−3) at month 15 from baseline. The PROUD study results have been reported as negative by preliminary presentations.13,67


Potential Limitations of Delayed-start Trial Designs There are a number of concerns regarding delayed-start study designs that may affect the quality of results. The delayed-start group (i.e., patients who receive placebo during Phase 1) foregoes symptomatic therapy for the first half of the study. In clinical trials assessing the treatment of slowly progressing diseases such as PD, the first half of the study normally lasts 6−9 months, which is a long time for a patient to be without symptomatic therapy. Moreover, most patients, when newly diagnosed with PD, already require treatment to control symptoms, thus reducing the pool of potential


97


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108