Endpoints and Analyses to Discern Disease-Modifying Drug Effects in Early Parkinson’s Disease

Abstract

Abstract. Parkinson's disease is an age-related degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech, as well as other functions. Symptoms can include tremor, stiffness, slowness of movement, and impaired balance. An estimated four million people worldwide suffer from the disease, which usually affects people over the age of 60. Presently, there is no precedent for approving any drug as having a modifying effect (i.e., slowing or delaying) for disease progression of Parkinson's disease. Clinical trial designs such as delayed start and withdrawal are being proposed to discern symptomatic and protective effects. The current work focused on understanding the features of delayed start design using prior knowledge from published and data submitted to US Food and Drug Administration (US FDA) as part of drug approval or protocol evaluation. Clinical trial simulations were conducted to evaluate the false-positive rate, power under a new statistical analysis methodology, and various scenarios leading to patient discontinuations from clinical trials. The outcome of this work is part of the ongoing discussion between the US FDA and the pharmaceutical industry on the standards required for demonstrating disease-modifying effect using delayed start design.

The current role of model-based drug development

“…The current role of model-based drug development optimizing development time and resources [24,25]. This approach supports quantitative integration of information across different species in preclinical development and throughout the clinical Phases I --III [26].…”

Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency

“…Disease modification has been most extensively studied in neurological diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis which, like AATD, are chronic, slowly progressing diseases. Some of these studies utilised a withdrawal trial design where patients are randomised to either placebo or active treatments and subsequently all patients are switched to placebo (23,24). For example, in one study patients with Parkinson's disease were followed for 3 months during washin and for 2 months during washout (withdrawal period) (25).…”

“…In the first phase patients are randomised to receive either placebo or active treatment, as in classical placebo-controlled, parallel group study design, but differences in study endpoints between the two groups at the end of this phase could be due to symptomatic effects or short-term benefits and not due to disease modification. In phase 2, both groups receive active treatment; if a difference in a study endpoint remains at the end of this stage a treatment may be considered to be disease-modifying (23,24). This trial design has been used effectively to study the effect of rasagiline, a monoamine oxidase type-B inhibitor, in the treatment of Parkinson's disease (26).…”

Unmet needs in Parkinson's disease: New horizons in a changing landscape

“…Without validated biomarkers of disease, it is virtually impossible to prove an effect on the underlying disease progression. Recent experience with the rasagiline ADAGIO trial [36] showed us that it can be very hard to interpret clinical data, no matter how sophisticated the trial design is [37,38], and the availability of a biomarker is now considered a pre-requisite for the development of new disease-modifying treatment strategies for PD [39,40]. Moreover, since patients already have undergone significant neurodegeneration before they develop overt motor symptoms, treatment at diagnosis may already be too late for a neuroprotective agent.…”