The Evidence for Disease Modification in Parkinson's Disease

ABSTRACT

Disease modification or slowing the progression of any neurodegenerative disorder represents a dire unmet need. There have been trials for several decades specifically designed to help evaluate whether a specific therapy might be able to slow the progression of Parkinson's disease (PD) or be disease modifying. Trials evaluating the use of coenzyme Q10, pramipexole, and levodopa suggest that these medications offer symptomatic benefit uniquely, while other studies reveal that rasagiline and selegiline may be disease modifying. This review will discuss in detail the design and results of clinical trials for varied medical therapies that were specifically undertaken to discern whether a particular treatment might be disease modifying in the treatment of PD.

KEYWORDS: :

• clinical trials
• Parkinson's disease (PD)
• neuroprotection

Parkinson's disease (PD) was first described almost two centuries past by the family practitioner James Parkinson [1]. His clinical acumen was extremely apparent, as his depiction of both the motor and the nonmotor features of this disorder remain accurate to date. He addressed the need for therapy as follows: “Until we are better informed respecting the nature of this disease, the employment of internal medicines is scarcely warrantable” (pg 62) [1]. He also noted that “on the subject of causes, no remote account has yet been obtained from any of the sufferers” (pg 35) [1]. As we move forward in time, now almost 200 years after this brilliant narrative, still without knowledge of the definitive cause of PD, this greatly complicates our capacity to develop and subsequently refine therapeutic interventions that might offer radical, long-term, if not true neuroprotective, benefit.

Over decades, clinical treatments for PD have been available and used with varying degrees of success, which is of course dependent upon how success is measured or simply construed. While many seemingly effective medications exist, none offer the promise of ongoing continued, robust, symptomatic benefit in the face of disease progression. Additionally, the development of sequelae of therapy in the way of motor fluctuations may be as difficult, if not more, to treat than the underlying disease. These issues frequently monopolize a clinician's time and a patient's needs. To date, no therapy, medical or surgical, can offer the promise of turning back the clock of disease progression indefinitely.

Disease modification or slowing the progression of any neurodegenerative disorder represents a dire unmet need. It would make sense that a therapy to ultimately slow clinical disease progression in a measurable/apparent fashion truly represents a “Holy Grail.” Inexorable progression, whether slowly progressive or fulminant, has become the all too established pattern when we conjure a visual conceptualization of neurodegeneration in clinical medicine. As such, for decades, we have been plodding along with treatments that offer symptomatic benefit of varying degrees.

In an effort to be able to address this very complex issue, basic research studies in either cell culture or in rodent and primate models of PD were undertaken. Medications such as selegiline [2], rasagiline [3], pramipexole [4], and coenzyme Q10 (CoQ10) [5] were shown in various preclinical paradigms and models to offer neuroprotective qualities. It thus made sense to proceed to human trials with many of these agents, with a firm basis in preclinical work to support this advancement. Typically, the term “neuroprotection” has been used to specifically refer to a decrease in cell death, as measured quantitatively in preclinical models where such measurement is possible. In human clinical trials, the term “disease modification” may be used more accurately as we are unable to do these sophisticated quantifiable cell count measures, which are only possible in sacrificed animals. These terms, however, can be found in the literature at times being used interchangeably.

TRIALS INVESTIGATING THE USE OF MAO-B INHIBITORS

In 1989, the preliminary results of the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy for Parkinson's Disease) study [6], the largest study in early PD at the time, were reported. This trial commenced in 1987 and randomized 800 study subjects in a double-blind, placebo-controlled, multicenter trial, in which they were assigned to receive either placebo, selegiline (an MAO-B [monoamine oxidase type B] inhibitor) and tocopherol (a component of vitamin E that traps free radicals), active selegiline and tocopherol placebo, or selegiline placebo and active tocopherol. The primary outcome of the study was the onset of disability, necessitating the initiation of levodopa therapy. The interim analysis revealed that of the 399 patients randomized to receive either selegiline alone or with placebo and of the 401 who received tocopherol or placebo, the risk of reaching endpoint was reduced by 57% in the groups receiving selegiline. Only 97 of the selegiline patients reached endpoint, thus needing L-dopa therapy at 12 months, compared with 176 who did not receive selegiline (p<10⁻⁸). There was also a significant reduction in the risk of needing to terminate full-time employment (p<.01) in the selegiline group. The conclusion based on this preliminary analysis by the Parkinson's Study Group suggested that the use of selegiline delayed the onset of disability in early PD [6].

The cohorts were followed for an additional 14 ± 6 months and the results of the tocopherol and selegiline groups were subsequently reported [7]. Treatment with tocopherol did not reduce the risk compared with placebo in reaching the endpoint. Kaplan–Meier plots of the probability of reaching endpoint between selegiline and non-selegiline groups differed significantly (p<.001) (Figure 1). There was an approximate difference of almost nine months between the two groups in time to reaching the endpoint of need for levodopa. For subjects who did not reach the endpoint (survivors), after two months of selegiline withdrawal, Unified Parkinson's Disease Rating Scale (UPDRS) total scores showed a significantly slower decline compared with other groups.

FIGURE 1.  The hazard ratio for the comparison of subjects taking deprenyl (with placebo or tocopherol) with subjects not taking deprenyl (placebo only or tocopherol with placebo) with respect to the risk of reaching the end point per unit of time is 0.50 (p < 0.001; 95 percent confidence interval, 0.41 to 0.62). The period of analysis was the time from base line to the last evaluation during treatment. The number of subjects evaluated in each group is shown under each time point. (Reproduced with permission from Reference [7]).

Additionally, comparing UPDRS motor subscales during the first three months of treatment versus after two months of study drug washout, motor scores in the selegiline group showed a significant difference (p < .001) versus placebo groups, but still showed some decrease in benefit in the selegiline group over time. This implies, at least in part, a clinically symptomatic effect of selegiline. The fact that there was a significant delay of the selegiline group in meeting the primary endpoint and that the group did not need selegiline added during a two-month washout suggest a potential “protective” influence, as per the Parkinson's Study Group [7]. Results of the three-year follow-up of the DATATOP cohort revealed that the original benefit seen in the selegiline group did not persist. [8,9]. After three years, or 18 months of open-label follow-up in this cohort, there was no evidence that early randomization to selegiline delayed the onset of the need for levodopa or reduced the rate of worsening of UPDRS scores. In fact, those who received selegiline during the initial randomization showed more rapid progression during open-label testing. Additionally, levodopa-induced motor fluctuations were similarly evident in the selegiline-treated original group as in the placebo group. Hoehn and Yahr, and Schwab and England scores, and the development of wearing off were all more severe in the group originally randomized to selegiline. Moreover, the dose of levodopa was similar in both groups. This longer-term follow-up suggested that the benefit seen earlier did not persist, as would be expected if, in fact, this therapy produced a disease-modifying effect.

This issue still remains controversial, as a more recent study performed by the Swedish Parkinson's Study Group again suggested that selegiline might slow the progression of PD [10]. In a cohort of 140 PD patients followed for five years, randomized to receive placebo or selegiline and then L-dopa as needed, the placebo cohort necessitated a 19% higher dose of L-dopa and presented with UPDRS motor scores that were 10 points higher at five years. These results found significant motor improvement and decreased need for L-dopa with long-term selegiline use in this naturalistic setting. Given the results of the DATATOP study's three-year follow-up [8,9] showing no enduring beneficial differences in the selegiline group, this Swedish trial once again piqued interest in the use of this MAO-B inhibitor in early PD.

DELAYED-START PARADIGM IN EARLY PD

In 1997, Dr Paul Leber, working for the FDA, wrote a seminal article in an attempt to redefine the methodology employed to determine whether a therapy might slow the progression of Alzheimer's disease [11]. In this work, the author detailed the shortfall of the withdrawal design, as utilized in DATATOP and other smaller selegiline trials [12]. He reviewed the problematic approach to the withdrawal protocol in determining the proper duration of placebo therapy prior to determining whether an effect is maintained or lost. He described the hardship this places on patients and families, the “unattractive” nature this presents, and the difficulties this brings forth with recruitment.

An alternative paradigm was described, in which patients were randomized to receive therapy versus placebo, and instead of “withdrawing” a potentially effective therapy, the initial placebo group was then subjected to therapy in a “randomized-start” fashion. If the initial placebo group that was treated after a delay was then compared with the group that was treated upon trial initiation and if it rapidly reached the same level of improvement, this was considered a “symptomatic” intervention. If the initial placebo group did not achieve the same level of improvement as achieved by the initially treated group, this was considered to be a “structural” improvement in the initially treated group, which could not be equaled by the initial placebo group potentially because there was a disease-modifying effect of the initial treatment.

This approach, using a “delayed-start design” [13] (Figure 2) to help disentangle the symptomatic effect of a therapy from its disease-modifying effect, was employed in the TEMPO (TVP-1012 [an early name for rasagiline] in Early Monotherapy for Parkinson's Disease Outpatients) [14] trial evaluating the use of a new generation MAO-B inhibitor, rasagiline, for the treatment of early PD. In this trial, 398 patients with early PD, defined during this trial as about one year on average from diagnosis, were randomized to receive either placebo, 1 mg of rasagiline, or 2 mg of rasagiline for six months. Inclusion criteria for this trial allowed patients to continue taking an anticholinergic but no other PD medication prior to study initiation. After the placebo-controlled trial portion, an active treatment trial ensued for the next six months, during which the initial/early treatment randomizations for the rasagiline groups were continued, but the initial placebo group then received 2 mg of rasagiline [15] (Figure 3).

FIGURE 2.  In both panels shown here, the active medication provides a benefit in comparison with placebo. (A) Symptomatic: the substitution of placebo with the active drug (delayed-start) provides a benefit that allows the group to “catch up” with the early-start group, showing a similar improvement in disability at the end of phase B—this outcome is in favor in a purely symptomatic effect. (B) “Disease-modifying”: the delayed introduction of the active drug after placebo does not provide a benefit euqal to that observed when patients start active treatment early, and the difference persists throughout phase B. This result shows that patients starting therapy early did better than those who started late, and cannot be explained by a simple symptomatic effect. It is in favor of a disease-modification effect, regardless of the fact that this could be due to “neuroprotection” or enhancement of early compensatory mechanisms. (Reproduced with permission from Reference [13]).

FIGURE 3.  Mean (± 1 SE) change in the Unified Parkinson's Disease Rating Scale (UPDRS) score for each group. A, Total unadjusted UPDRS score by visit for each treatment group for the 371 subjects included in the efficacy cohort. For the efficacy cohort, the last observation was carried forward for subjects with missing values for a given visit. (Reproduced with permission from Reference [15]).

Results of this trial revealed that rasagiline showed similar clinical efficacy at six months for both doses compared with placebo and was well tolerated. The authors proposed that the results of the 12-month follow-up “suggests that the effects of rasagiline on the progression of disability in patients with PD cannot be fully explained by its symptomatic effect and may be due to a disease-modifying activity of the drug” (pg 565) [15]. This cohort was followed long term in an open-label study for more than six years [16]. Results revealed that at all time points, the early-start group had numerically better values compared with the delayed-start group. There was a mean change of 16% from baseline in the UPDRS total score between the delayed-start and the early-start group over the entire 6.5-year period (Figure 4). Based on the 12-month TEMPO data and the supportive long-term follow-up data, another very large trial, ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily), was designed to more definitively determine whether, in fact, treatment with rasagiline in early PD might represent a disease-modifying therapy [17].

FIGURE 4.  Mean percent change from TEMPO baseline in total UPDRS scores: early-start versus delayed-start with rasagiline (N = 404). Overall difference between early-start and delayed-start groups is 16% (RMA; p = 0.006). Numbers in parentheses () represent numbers of subjects remaining on rasagiline at each time point. The analysis of UPDRS scores was performed at each time point according to available patient visits, and not necessarily synchronized with TEMPO placebo-controlled and active-treatment phases shown in Figure 1. Bars indicate standard errors. Data from year 6.5 are combined with data from year 6. (Reproduced with permission from Reference [16]).

To help tease apart the issue of a symptomatic effect accounting for the slowing of decline of the UPDRS mean scores versus a neuroprotective/disease-modifying effect, the FDA required a more complex constellation of primary variables, including a complex statistical analysis based on a hierarchical slope analysis of various phases of the ADAGIO trial. This study utilized a delayed-start design and enrolled 1,176 patients with early PD who on average were only 4.5 months out from their diagnosis. Patients were not taking any PD medications upon entry into the trial, and the placebo-controlled and active treatment portions were each nine months long. There were three primary variables, including firstly, the superiority of the slopes in the placebo-controlled phase; secondly, the mean change in UPDRS scores comparing delayed-start versus early-start groups from baseline to 72 weeks; and finally, the noninferiority of the slopes during the active phase. In order for this to be a positive trial, all three primary variables needed to be reached hierarchically. In the ADAGIO trial, patients were randomized to receive 1 mg rasagiline versus 2 mg rasagiline versus placebo.

The results revealed that the 1-mg-dose group met all three predefined variables, while the 2-mg-dose group did not (Figure 5). It is visibly evident from Figure 5 that the 2-mg-dose group did not show any difference at 72 weeks between the early-start and the delayed-start group with regard to UPDRS scores as the lines clearly meet in the figure. The authors suggest that a “marked effect of the 2 mg dose on symptoms might have masked a benefit associated with early treatment in this population of patients with very mild disease” (pg 1273) [17]. In fact, they go on to show that a post-hoc analysis of patients with the highest 25% of UPDRS scores in the group (more advanced disease) actually meet all three predefined endpoints. This provides evidence to suggest that a symptomatic effect at the 2-mg dose may have masked a more subtle disease-modifying effect in this cohort. Additionally, the positive results of the post-hoc analysis reviewing the results of the top-quartile UPDRS scores in the 2-mg-dose group suggest the possibility of a “floor effect” in this group impacting the outcome. It should also be noted that the 2-mg dose is not FDA approved for use, and that the data would confirm no clinical efficacy of this dose over the approved 1-mg dose. The authors of this trial suggest “a possible benefit of the early use of rasagiline at a dose of 1 mg per day; however, given the negative findings for the 2-mg dose, we cannot definitively conclude that rasagiline at a dose of 1 mg per day has disease-modifying effects” (pg 1277) [17].

FIGURE 5.  The mean (±SE) change from baseline in the UPDRS score in the efficacy cohort for the second and third primary end points for patients receiving rasagiline at a dose of 1 mg per day (Panel A) and those receiving 2 mg per day (Panel B) are shown. The dashed lines indicate placebo, and the solid lines indicate rasagiline. (Reproduced with permission from Reference [17]).

The previous rasagiline trials, TEMPO/long-term TEMPO and ADAGIO, designed as delayed-start studies, both suggested that early treatment with rasagiline offered significant benefit compared with placebo, and that earlier treatment compared with “delayed treatment” offered benefit that was longstanding.

PRAMIPEXOLE IN A DELAYED-START TRIAL

Another delayed-start design study, the PROUD (Assessment of Potential Impact of Pramipexole On Underlying Disease) study [18], was performed to help determine whether pramipexole might be a disease-modifying therapy in early PD. In total, 535 early-PD patients, on average 4.4 months from diagnosis, were randomized to receive pramipexole (0.5 mg t.i.d.) versus placebo for 6–9 months. The active treatment phase was carried out up to 15 months, with the delayed-start/initial placebo group then receiving pramipexole. The primary endpoint was the change in UPDRS score between the two groups at 15 months. Additionally, a group of patients (n = 150) in Europe had dopamine transporter (DAT) SPECT (single-photon emission computed tomography) scanning to better explore the underlying mechanism of action of this medication.

Results of the PROUD trial [18,19] revealed that there was no difference between the early-start and the delayed-start group at 15 months. Similar results were found with the neuroimaging (SPECT) group. There was no difference in DAT imaging results (comparing baseline with 15 months) between the early-start and the delayed-start group. These results confirm that simply starting any therapy early in a delayed-start design will not confer positive results.

A TRIAL INVESTIGATING CARBIDOPA/LEVODOPA AS DISEASE MODIFYING

A trial (ELLDOPA: Earlier versus Later Levodopa in Parkinson Disease) evaluating whether or not carbidopa/levodopa (CD/LD) might slow or hasten the progression of PD included 360 early-PD patients randomized to receive half a tablet of 25/100 CD/LD t.i.d. (150 mg total daily dose) versus one tablet of 25/100 CD/LD t.i.d. (300 mg total daily dose) versus two tablets of 25/100 CD/LD t.i.d. (600 mg total daily dose) versus placebo for 11 months [20]. The primary endpoint was the difference in the UPDRS total score comparing baseline with 11 months across all doses. While a definite dose response curve was evident with the higher dose fairing the best and placebo group with the worst scores as might have been predicted, the 600 mg dose group suffered the most prominent adverse events with 16% displaying dyskinesias and 30% displaying wearing off by study end (11 months).

Additionally, at the end of 11 months, CD/LD was withdrawn for two weeks. Over this time period, the UPDRS total scores in all of the dose groups remained lower (better outcome) than the placebo group, again in a dose–response fashion. These results suggested that levodopa is not neurotoxic and may be neuroprotective. The most viable explanation for this finding is most likely that the clinical symptomatic response of levodopa extended beyond the two-week period of washout. A subset of this cohort was evaluated using β-CIT SPECT scanning, which functions as a surrogate marker for intact nigrostriatal dopaminergic neurons by labeling the DAT. The results of the neuroimaging studies showed that there was a larger decrease in nigrostriatal DAT binding in the levodopa-treated groups compared with the placebo group. This result presented a confusing picture when reconciling the imaging with clinical data, as the patients who received L-dopa did better in a dose–response fashion, yet the SPECT scans of these patients treated with L-dopa suggested greater dopaminergic deterioration. The authors proposed that “it is possible that the observed changes in the levels of uptake of this marker reflected a pharmacological effect of levodopa on DAT activity, rather than evidence of injury to dopaminergic neurons” (pg 40) [21].

CoQ10 TRIALS IN EARLY PD

Patients with PD have been shown to have lower serum and platelet levels of CoQ10 and reduced mitochondrial complex 1 activity, wherein CoQ10 functions as a co-factor [22]. Both clinical and preclinical trials provided evidence for evaluation of CoQ10 use in PD and suggested a role of mitochondrial dysfunction in the pathogenesis of PD [23,24]. A pilot dose-ranging trial (Coenzyme Q10 Evaluation-2 [QE2]) studying three doses, 300 mg vs. 600 mg vs. 1200 mg of CoQ10 vs. placebo, was undertaken, enrolling 80 patients with early PD not previously treated with other agents [25]. The cohort was followed for 16 months. This trial showed that the lower doses were no more effective than placebo. While the primary analysis of this trial was a “linear trend between dosage and the mean change in UPDRS”, only the 1200-mg dose showed a positive trend. It was concluded by the authors that a significant decrease in functional decline was seen in the highest-dose group and “slowing of the worsening as measured by the UPDRS scores.” A much larger, placebo-controlled trial of approximately 600 early-PD patients was initiated (QE3) [26]. The cohort in this trial was randomized to receive placebo vs. 1200 mg vs. 2400 mg of CoQ10 and was to be followed for 16 months. The primary variable was the change in UPDRS total score at 16 months. Recent release of an interim analysis of this trial by the Data Safety Monitoring Board found that it would be futile to complete the study and unlikely to show a difference between CoQ10 treatment and placebo. As such, the trial was terminated prematurely [27].

NEUROPROTECTION EXPLORATORY TRIALS IN PD (NET-PD)

In an attempt to fast-track and streamline the search for neuroprotective trials in PD, an NIH (National Institutes of Health) consortium, Neuroprotection Exploratory Trials in PD (NET-PD) Investigators, was formed. A futility design was employed to rapidly evaluate a series of agents as potential candidates. The first trial (FS-1) evaluated creatine and minocycline [28]. The primary outcome was the change in the UPDRS total score from baseline to either the time when there was sufficient disability to warrant symptomatic therapy for PD or 12 months, whichever came first. Two hundred subjects were randomized to receive creatine 10 g/day, minocycline 200 mg/day, or matching placebo. The futility threshold was set as a 30% reduction in UPDRS progression based on the placebo/tocopherol arm of the DATATOP trial. Neither creatine nor minocycline could be rejected as futile based on the DATATOP futility threshold.

A second futility study reviewed the effects of CoQ10 and GPI-1485, a neuroimmunophillin [29]. One hundred and thirty-nine patients were randomized to receive either agent or placebo. The results similarly showed both agents were nonfutile when compared with the DATATOP control set. When a separate analysis was done using a current control cohort, of the four agents tested in the two futility trials, only creatine was found to be nonfutile and suitable for a more extensive evaluation in a larger, long-term simple study. To better analyze the effect of creatine on longer-term cumulative disability, a double-blind, placebo-controlled trial, called LS-1, evaluating 1,700+ patients within five years from diagnosis is underway. This cohort was randomized to receive either placebo or 5 g of creatine b.i.d. and will be followed over five years, with the primary endpoints including motor function, activities of daily living, gait, falling, balance, quality of life and measures of cognition [30].

EXERCISE STUDIES IN PD

Finally, the results of high-intensity exercise in preclinical models of PD suggest that this may be a neuroprotective/disease-modifying therapy. MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) mice run in a motorized treadmill exercise paradigm showed that pretreatment with exercise prior to lesioning and then exercising after lesioning protected against dopaminergic cell loss and allowed for restoration of dopaminergic function, respectively [31]. In human exercise trials, patients with early PD who underwent high-intensity bodyweight-supported treadmill training showed improved exercise parameters and normalization of cortico-motor excitability, as measured by transcranial magnetic stimulation [32]. This body of literature suggests that the exercise-induced alterations in dopaminergic and glutamatergic neurotransmission may mitigate against the cortically driven hyperexcitability of the basal ganglia normally seen in the parkinsonian state [33]. To date, there have been no conclusive trials confirming exercise in PD patients to be disease modifying, and no large multicenter, placebo-controlled trials evaluating the potential disease-modifying effects of exercise in PD have been performed. Such trials are, however, currently being designed (G. Petzinger, M. Jakowec, Personal Communication, September 23, 2011).

OTHER TRIALS EVALUATING DISEASE MODIFICATION IN PD

There are several new studies underway to continue the search for disease-modifying therapies. Basic research trials on an MPTP rodent model suggest that the calcium channel modulator, isradipine, is protective of dopaminergic deterioration in the substantia nigra [34,35]. A preliminary placebo-controlled trial evaluating three doses of isradipine in early-PD patients is currently underway (STEADY-PD: Safety, Tolerability and Efficacy Assessment of Dynacirc CR in Parkinson Disease) [36].

Finally, a preliminary trial of inosine, a urate precursor, is underway to determine whether this is a safe compound to evaluate as a possible disease-modifying therapy in PD (SURE-PD: Safety and Ability to Elevate Urate in Early Parkinson Disease) [37]. Urate has potent antioxidant properties [38], and preclinical trials show it to be neuroprotective in the MPTP rodent model [39]. Epidemiologic studies suggest that lower urate levels increase the risk of PD and higher levels may decrease PD risk [40]. The SURE-PD study is a placebo-controlled, dose-finding, safety and tolerability trial studying the effects of inosine in early PD.

SUMMARY

In summary, we remain in a relatively unique position, treating this progressive degenerative neurologic disorder without a firm understanding of the underlying etiology. This has impacted our capacity to design focused trials to potentially and definitively slow the progression and/or reverse central abnormalities. Past trials provide evidence that the MAO-B inhibitors, selegiline and rasagiline, may possibly modify the outcome of PD, while studies with pramipexole, levodopa, and CoQ10 have had negative results. As we move forward, we are concentrating efforts to tease out potential disease-modifying endpoints and paradigms, and engaging new therapies that may provide true neuromodulating effects. We are in grave need of treatments for PD that slow the progression of this disease and may offer improved function and quality of life and more robust, consistent benefit, which may persist without the risk of return of worsening fluctuations.

Declaration of interest: Speaker: Boehringer-Ingelheim, Teva, Eisai/Solstice Neurosciences, Ipsen. Advisor/consultant: Teva, BI, Solstice Neurosciences, Novartis, Ipsen, Schering Plough, GSK, Eisai, Mentor/Johnson & Johnson, Merz. Researcher: NIH, Abbott/Solvay, Schering Plough, Parkinson Study Group, Michael J. Fox Foundation, Allon Therapeutics, Addex, Takeda Pharmaceuticals, Ipsen, Synosia Pharmaceuticals. Foundation grants: National Parkinson's Disease Foundation (NPF), HollyRod Foundation