Published Online: September 22, 2012
Daniel L. Murman, MD, MS, FAAN
The diagnosis and treatment of Parkinson’s disease (PD) typically occur when the disease has already progressed to a relatively advanced stage in which motor symptoms are clearly evident and substantial neurophysiological damage has already taken place. Nonmotor symptoms, which account for a large proportion of PD symptoms, usually emerge much earlier and offer both an early indication for treatment and a therapeutic target. A growing body of data from the medical literature points to several critical advantages that may be associated with early therapeutic intervention in PD. The most evident benefit of early intervention is a reduction in symptoms, particularly dyskinesia, and the delay of levodopa initiation. Clinical trials suggest but have yet to conclusively demonstrate that early treatment can slow disease progression. Both the diminishment of symptoms and the potential for slowing disease progression have large implications for improving patient quality of life. The enormous direct costs associated with PD would also likely be reduced over the long term with earlier treatment. The great majority of costs attributable to PD occur when the disease is at its most advanced stage and when symptoms are most severe. An early-treatment strategy that diminishes symptoms and that has the potential to slow disease progression could have a meaningful impact on PD expenditures. Adherence, too, must be taken into consideration, particularly since PD patients are generally poorly adherent to prescribed therapies, especially therapies with complex dosing schedules. Taking advantage of more convenient and adherencefriendly drug formulations may further help to improve outcomes and lower costs in PD.
(Am J Manag Care. 2012;18:S183-S188)
Early Treatment: Benefits and Options
Parkinson’s disease (PD) has traditionally been diagnosed and treated when the disease has already progressed to a fairly advanced stage. In recent years, however, the potential benefits of early intervention in PD have been recognized. The primary rationales for early initiation of treatment in patients with PD include slowing disease progression, delaying and diminishing symptoms (both motor and nonmotor), limiting deterioration of patient quality of life (QoL), and achieving long-term cost savings.
Slowing Disease Progression
Patients with PD who remain untreated, or insufficiently treated, will experience ongoing and substantial symptomatic deterioration and negative effects on their QoL.1,2 Based on relative QoL scores, PD rates as one of the most severe chronic diseases in terms of physical, functional, mental, and social burdens.2 Although motor symptoms are the most recognizable of symptoms in PD, and are those upon which a PD diagnosis is largely contingent, nonmotor symptoms represent not only a large proportion of overall PD symptoms but, in many cases, emerge earlier than motor symptoms. Indeed, nonmotor symptoms have been shown to exert a greater negative influence on QoL than motor symptoms.3,4 Three nonmotor symptom domains—apathy, attention/memory, and psychiatric symptoms—have been seen to emerge early in the disease and, thus, offer not only a rationale for early intervention, but also a potential means of identifying patients requiring early intervention.5 Similarly, sleep disruption and constipation are early and potentially treatable nonmotor symptoms of PD.6
The fundamental goal of early treatment for patients with PD is slowing the progression, and the symptomatic manifestations, of the disease. However, slowing disease progression in PD is an exquisitely complex endeavor for several reasons. First, defining what exactly is meant by slowing disease progression is itself a multifaceted issue. Secondly, measuring success in the slowing of disease progression—almost regardless of how that goal is defined—is extremely difficult, and, in some cases, currently impossible. With those limitations in mind, how can we understand what slowing disease progression entails? This question might be approached by considering the appropriate means of measuring disease progression.
The standard means of measuring PD progression is the Unified Parkinson’s Disease Rating Scale (UPDRS), an instrument that is widely used for measuring treatment success in clinical trials.7 The UPDRS, however, is less than ideal in the context of measuring disease progression because it is an instrument largely limited to defining the status of symptoms, and motor symptoms in particular. The problem here is 2-fold: 1) nonmotor symptoms, as previously noted, represent a large part of the symptomatic experience of people with PD, and 2) measuring symptoms does not provide all the necessary information needed to determine disease progression.5 It should be noted that a newer version of the UPDRS has been developed to evaluate a wider spectrum of symptoms, although its clinical utility remains untested.8
It may be the case that neuroimaging studies—for example, single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and positron emission tomography (PET)—offer a more valuable, or at least necessarily additive, perspective on disease progression. However, the utility of these modalities as biomarkers for evaluating the efficacy of therapeutic interventions to slow disease progression remains imperfect, and additional development is necessary to make them fully useful and integrate them into clinical practice. Indeed, for both SPECT and PET, there exists an ongoing debate as to whether changes in radioligand uptake do in fact measure nigralstriatal integrity (or neuronal loss) or simply the effects of medications on synaptic activity.
Two terms often used in the context of slowing disease progression are “neuroprotection,” which refers to effecting a change in the pathophysiology of PD, and “disease modification,” which would typically refer to an effect upon clinical outcome that is not contingent upon an absolute change in PD pathophysiology.9 However, a lack of consensus on this terminology in the PD setting makes the use of the term “disease modification” potentially confusing. Therefore, for the remainder of this article, the term “outcome modification” will be used to describe a therapeutic intervention that produces a positive change in clinical outcome without necessarily affecting disease pathophysiology.
It is generally accepted that neuroprotection as a consequence of therapeutic intervention in PD has not yet been demonstrated, although this does not necessarily mean it has not been achieved. Part of the problem in establishing whether a treatment is neuroprotective has to do with designing and executing a clinical trial that is up to the very challenging task of proving neuroprotection.10 Preclinical studies have the advantage of allowing for measurement of neuronal loss, but this is not, at present, possible in live human patients.11 Thus, human clinical trials that attempt to measure neuroprotection must do so indirectly. A discussion of the complexity of trial design to determine neuroprotection is beyond the scope of this article; however, Henchcliffe and Severt have provided a useful overview of the subject.12
Investigators have employed various clinical study designs in an attempt to accurately determine whether a given agent offers outcome modification and/or neuroprotection in PD. The lack of proven biomarkers to allow for clear confirmation of such end points makes this task very challenging, and different approaches have been tried in order to overcome these limitations.
The Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial was a placebo-controlled, double-blind study that employed a delayed-start study design as a means of evaluating the capacity of the MAO-B inhibitor rasagiline to confer outcome-modifying effects in early PD patients. The ADAGIO study population included 1176
untreated subjects with early PD who were randomized to receive either 1 mg per day or 2 mg per day for 72 weeks (designated the “early-start” groups) or to receive placebo for 36 weeks followed by 1 mg or 2 mg rasagiline for the following 36 weeks (designated the “delayed-start” groups).13 The ADAGIO study included 3 primary end points. The first primary end point was change in UPDRS points per week, also known as the “slope,” which was the primary means of measuring disease progression in the 4 treatment groups. The second primary end point was a comparison between the earlystart and delayed-start groups for estimated change in UPDRS from baseline to week 76, which was intended to measure if initial benefits gained by patients in the early-start groups were sustained at the end of the study, which would also tend to indicate positive outcome modification. The third primary end point was noninferiority of slope during weeks 48 through 72 for the early- versus delayed-start group, ie, if benefits gained during the second 36-week period remained as robust in the early-start group versus the delayed-start group, this would indicate an enduring positive outcome effect resulting from the early-start strategy.13
The ADAGIO trial, in seeking to maintain a type I error of 0.05 across a study that involved 3 primary end points and 2 separate doses in each group, employed a hierarchical design, such that each of its primary end points had to be met for the results to be deemed positive for either of the 1 mg or 2 mg doses.10,13 At the end of the study, early-start patients receiving 1 mg had achieved all 3 primary end points, while the 2 mg group, though it did achieve the first and third end points, did not achieve the second primary end point.10
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