A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes (original) (raw)
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Movement Disorders, 2008
A neuroprotective therapy is the single most important unmet medical need in Parkinson's disease. Several promising agents in the laboratory have been tested in the clinic, but none has been established in clinical trials to have a disease modifying effect despite positive results because of potential confounding symptomatic or pharmacologic effects. The delayed start design was developed to try to avoid a symptomatic confound when testing a putative neuroprotective therapy. In this study design, patients are randomly assigned to study drug or placebo in the first phase of the study, and both groups receive the active drug in the second phase. If benefits seen at the end of phase I persist through the end of phase II, they cannot be readily explained by a symptomatic effect (as patients in both groups are receiving the same medication) and benefits in the early start group must relate to the early initiation of the treatment. Although the precise mechanism responsible for such an effect can be debated, positive results in a delayed start study indicate that patients who receive early treatment have a better outcome than those where
A Controlled Trial of Rasagiline in Early Parkinson Disease
Archives of Neurology, 2002
Patients: Patients with early PD not requiring dopaminergic therapy (n = 404). Intervention: Research participants were randomized to rasagiline mesylate at dosages of 1 mg or 2 mg per day or matching placebo. A 1-week escalation period was followed by a 25-week maintenance period. Main Outcome Measure: The primary prespecified measure of efficacy was the change in the total Unified Parkinson's Disease Rating Scale score between baseline and 26 weeks of treatment, comparing each active treatment group with the placebo group. Results: Monotherapy with rasagiline was effective in this 26-week study. The adjusted effect size for the total Unified Parkinson's Disease Rating Scale was −4.20 units comparing 1 mg of rasagiline and placebo (95% confidence interval, −5.66 to −2.73 units; PϽ.001) and −3.56 units comparing a 2-mg dosage and placebo (95% confidence interval, −5.04 to −2.08 units; P Ͻ.001). There were no meaningful differences in the frequency of adverse events or premature withdrawals among the treatment groups. Conclusions: Rasagiline is effective as monotherapy for patients with early PD. The 2 dosages in this trial were both effective relative to placebo. Further study is warranted to evaluate the longer-term effects of rasagiline in PD.
Movement Disorders, 2004
Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a potent, selective, and irreversible monoamine oxidase-B inhibitor. This study was designed to evaluate the safety, tolerability, and preliminary efficacy of rasagiline monotherapy in early Parkinson's disease (PD) patients not receiving levodopa. The study was performed as a multicenter, parallel-group, double-blind, randomized, placebo-controlled, 10-week study. Fifty-six PD patients were randomly assigned to rasagiline mesylate 1, 2, or 4 mg once daily, or placebo. A 3-week dose-escalation period was followed by a 7-week maintenance phase. At week 10, the mean (ϮSE) changes from baseline in total Unified Parkinson's Disease Rating Scale (UPDRS) score were Ϫ1.8 (Ϯ1.3), Ϫ3.6 (Ϯ1.7), Ϫ3.6 (Ϯ1.2), and Ϫ0.5 (Ϯ0.8) in the rasagiline 1, 2, and 4 mg/day and placebo groups, respectively. Analysis of responders showed that 28% of patients (12 of 43) receiving rasagiline had an improvement in total UPDRS score of greater than 30%, compared with none of the patients receiving placebo (P Ͻ 0.05, Fisher's exact test). The frequency and types of adverse events reported by rasagiline-treated and placebo-treated patients were similar. These results suggest that rasagiline monotherapy is well tolerated and efficacious in early PD.
Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease
Movement Disorders, 2009
The purpose of this study was to compare the long-term clinical outcome of early versus delayed rasagiline treatment in early Parkinson's disease (PD). Subjects (N 5 404) were randomly assigned to initial treatment with rasagiline (early-start group) or placebo for 6 months followed by rasagiline (delayed-start group) in the TEMPO study. Subjects who chose to participate in an open-label extension (N 5 306) continued to receive rasagiline as well as other PD medications as needed. Average (6SD) duration in the study was 3.6 6 2.1 years; 177 subjects received rasagiline for 5.0 years. Over the entire 6.5-year follow-up period, the adjusted mean difference in change from baseline in total UPDRS scores was 2.5 units (SE 1.1; P 5 0.021) or 16% (SE 5.7; P 5 0.006) in favor of the early-start versus delayed-start rasagiline group. Although the interaction between treatment and time was significant, values for the early-start group were better than the delayed-start group across all time points. Significantly less worsening (percent change) in total UPDRS scores was observed in the earlystart group at the time points 0.5, 1.5, 2.0, 3.0, 4.5, 5.0, and 5.5 years (P < 0.05). Compared to delayed start, early initiation of rasagiline provided long-term clinical benefit, even in the face of treatment with other dopaminergic agents. This might reflect enduring benefits due to neuroprotection or effects on compensatory mechanisms in early PD.
European Journal of Neurology, 2010
Rasagiline (Azilect 1) is a highly selective irreversible second generation MAO-B inhibitor indicated for the treatment of idiopathic Parkinson's disease (PD) as monotherapy or as adjunct therapy (with levodopa). The 6-month observational study included 871 patients to investigate the efficacy and tolerability of rasagiline in clinical daily practice focussing on non-motor symptoms and quality of life. Two thirds of the patients received 1 mg rasagiline daily as add-on to their regular PD-medication, the rest as monotherapy. Efficacy criteria were: (1) CURS, (2) PS-23 scale on Parkinson non-motor symptom strength, (3) UPDRS, part IV B, (4) duration of OFF-periods, (5) QoL by PDQ-8, (6) WHO-5 Well-being Index and (7) change of global clinical impression (CGI-I). Significant improvements have been observed in total severity of PD: PS-23 total score declined from 46.4 to 42.2. Health and general well-being measured by PDQ-8 improved significantly from baseline 16.3 to 14.3. Emotional well-being according to WHO-5 improved significantly from 14.4 to 16.4. Positive effects of rasagiline on motor symptoms have been observed: CURS total score improved significantly from 14.8 to 11.4. The proportion of patients without any OFF period increased from 47.1% to 59.1%. Patients reported that OFF periods decreased significantly, most pronounced the morning OFF. Rasagiline has shown to be effective either in monotherapy or in combination with L-Dopa, dopamine agonists or both. AEs were reported by 6.5% of the patients. The treatment with rasagiline in patients with PD resulted in improvements of motor and non-motor symptoms and led to an improved quality of life. 2015 Elsevier GmbH. All rights reserved.
Rasagiline and Rapid Symptomatic Motor Effect in Parkinson’s Disease: Review of Literature
Neurology and Therapy, 2013
Rasagiline is a monoamine oxidase type-B inhibitor used as monotherapy or in addition to levodopa in the treatment of Parkinson's disease. Once daily administration of rasagiline makes it easy to use, and allows good compliance by patients and adherence to therapy. Several multicenter studies have noted the effectiveness of rasagiline on both motor and non-motor symptoms, which require a complex pharmacologic approach, such as cognitive disorders. A recent study also reported a rapid action of rasagiline on motor symptoms. Positive findings have been highlighted by an economic model study. This review analyzes the main studies of rasagiline, with particular attention to the effectiveness of the drug on motor symptoms.
Randomized, Controlled Trial of Rasagiline as an Add-on to Dopamine Agonists in Parkinson's Disease
A B S T R AC T : 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 6 SD age was 62.6 6 9.7, and duration of PD was 2.1 6 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 6 SE, 22.4 6 0.95; 95% confidence interval [CI], 24.3, 20.5; P 5 0.012). Mean improvement (LS mean 6 SE) was 23.6 6 0.68 in the rasagiline group and 21.2 6 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.
Rasagiline improves quality of life in patients with early Parkinson's disease
Movement Disorders, 2006
The objective of this study was to determine the effects of rasagiline as monotherapy on quality of life (QOL) in patients with early Parkinson's disease (PD). Rasagiline, a potent, second-generation, irreversible, selective monoamine oxidase B inhibitor improves PD symptoms in patients with early PD. Patients with early untreated PD were randomly assigned to once-daily rasagiline 1 mg/day, rasagiline 2 mg/ day, or placebo in a 6-month, double-blind trial (n ϭ 404). At the end of 6 months, patients entered the preplanned, activetreatment phase in which those receiving 1 mg/day and 2 mg/day of rasagiline continued on their previously assigned dosages and those receiving placebo switched to rasagiline 2 mg/day, while maintaining blinding to treatment assignments. QOL was measured with the Parkinson's Disease Quality of Life questionnaire (PDQUALIF) at 0, 14, 26, and 52 weeks after randomization. Analysis of the change in PDQUALIF scores from baseline to 6 months showed adjusted treatment effects (with 95% confidence interval) favoring rasagiline over placebo of Ϫ2.91 units (Ϫ5.19, Ϫ0.64, P ϭ 0.01) for the 1 mg/day group and Ϫ2.74 units (Ϫ5.02, Ϫ0.45, P ϭ 0.02) for the 2 mg/day. Subscore analysis attributed most of this benefit to the self-image/sexuality domain. At 12 months (n ϭ 266), with all groups receiving rasagiline for at least 6 months, no significant differences in PDQUALIF scores were seen between groups. Rasagiline improved QOL compared with placebo. This QOL improvement appears to be accounted for primarily by the symptomatic benefit of rasagiline.
US Neurology, 2011
Various assessment scales are used to measure the severity and rate of progression of Parkinsons disease (PD)for example, the Unified Parkinson's Disease Rating Scale (UPDRS) and its Activities of Daily Living (ADL) subscale. The relative merits of these scales for accurately determining the degree of disease progression have recently come under scrutiny. Analyses of data from the recent Attenuation of disease progression with Azilect given once daily (ADAGIO) trial demonstrated that patients receiving early-start rasagiline (Azilect®, Teva Neuroscience, North Wales, PA) 1 mg/day experienced slower disease progression, as assessed by their mean total UPDRS score, than patients receiving placebo followed by delayed-start rasagiline treatment. Subsequent secondary analyses showed that 1 and 2 mg/day doses of early-start rasagiline delayed the need for antiparkinsonian drugs and improved other parameters, including ADL scores and fatigue, when compared with placebo followed by de...