The Right Therapy for Neurological Disorders

E. Beghi, G. Logroscino

• Publisher: S. Karger
• Year: 2016
• ISBN:
  9783318058659
• Topic: Medicina
• Subtopic: Sanità, amministrazione e assistenza pubblica

Most neurological disorders are chronic and aging-related. With the increase of life expectancy their incidence and prevalence will grow in the decades to come, which in turn will increase the load on medical and social systems worldwide. There is thus a desperate need for successful preventive and therapeutic measures based on randomized clinical trials (RTCs) conducted by independent organizations. This book provides a compendium relating most of the principles of reliable RTCs to specific neurological diseases. Contributed by specialized neurologists, the articles touch on important aspects of RCTs with a clear critical approach, highlighting their limitations as well as giving recommendations for their planning and conducting to address the variable genotypic and phenotypic aspects of neurological conditions. Consideration is also given to combining the clinical impact of the study results with patients' values and the interests of pharmaceutical companies. Neurologists involved in clinical trials will certainly benefit from this book, which should become a basic text for all neurological courses dealing with evidence-based neurology.

Beghi E, Logroscino G (eds): The Right Therapy for Neurological Disorders.
From Randomized Trials to Clinical Practice. Front Neurol Neurosci. Basel, Karger, 2016, vol 39, pp 8-23 (DOI: 10.1159/000445409)

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Peculiarities of Neurological Disorders and Study Designs

Ettore Beghi · Elisabetta Pupillo · Giorgia Giussani

Laboratory of Neurological Disorders, IRCCS-Mario Negri Institute for Pharmacological Research, Milan, Italy

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Abstract

Background: Neurological disorders are heterogeneous clinical conditions with variable course and outcome. Summary: The basic aspects of the commonest neurological disorders are addressed along with the proposed structure of randomized clinical trials (RCTs). Dementing disorders, including Alzheimer's disease (AD), are clinical conditions in which altered cognitive functions are associated with behavioral and personality changes. Parkinson's disease (PD) is a multisystem disorder characterized by motor dysfunction associated with dysautonomia, sleep and olfactory disturbances, cognitive changes, and depression. Amyotrophic lateral sclerosis (ALS) is an invariably fatal clinical condition involving motor neurons. The available treatments are purely symptomatic for PD but virtually ineffective for AD and ALS. Headache disorders, multiple sclerosis, and epilepsy, three diseases characterized by recurrent symptoms and chronic or episodic course, can be fairly easily controlled by current treatments, but cannot be prevented nor cured. The objectives of treatments of neurodegenerative disorders include primary prevention, slowing or arrest of disease progression, and control of symptoms. Stroke is an acute clinical condition causing frequent disability and death, with only one approved treatment. There are many challenges to acute stroke clinical trials; among them, the very short therapeutic window and the issue of stroke heterogeneity. In this chapter, only the core elements of the study designs are outlined. Key Messages: The design of an RCT must be adapted to the basic characteristics of each clinical condition.

© 2016 S. Karger AG, Basel

Neurological disorders are heterogeneous clinical conditions with variable course and outcome. Some of them are represented by acute monophasic entities with complete, partial, or no regression to baseline. Others are characterized by repeated episodes with return to the baseline conditions or, less frequently, with superimposed progression and accumulating disability. Others again have a relentless course with progressive worsening, albeit at differing speeds. All these peculiarities have a strong influence on the effects of treatments. For these reasons, the design of a randomized clinical trial (RCT) must be adapted to the basic characteristics of each clinical condition. In this chapter, the basic aspects of the commonest neurological disorders are addressed along with the proposed structure of RCTs. Only the core elements of the study designs will be outlined. A more comprehensive discussion of the characteristics of each disease can be found in the subsequent chapters. Those who are interested in having more information on the aims and structure of RCTs for selected neurological conditions are encouraged to read the guidelines on medicinal products issued by the European Medicines Agency (EMA) (http://emea.europa.eu) and the Iuphar Compendium of Basic Principles for Pharmacological Research in Humans (www.iuphar.org) that inspired the contents of this chapter.

Alzheimer's Disease and Other Dementias

Dementing disorders are a variety of clinical conditions characterized by progressive loss of cognitive functions, including memory, orientation, and language, and changes in personality and behavior. The commonest cause of dementia in the elderly is Alzheimer's disease (AD), followed by vascular dementia [1]. These two disorders partly overlap and can be considered the two extremes of a spectrum [2]. Other distinct forms of dementia include frontotemporal dementia, Parkinson's disease (PD) with dementia, dementia with Lewy bodies, and dementia associated with Huntington's disease. Each of them requires distinct diagnostic criteria [3]. Dementia may rarely occur in other clinical conditions including traumatic brain injury, schizophrenia, multiple sclerosis (MS), Creutzfeldt-Jakob disease, toxic and metabolic encephalopathies, and central nervous system (CNS) infections [3]. The diagnosis of dementia remains primarily clinical. Dementia must be distinguished from mild cognitive impairment (MCI), a memory complaint, preferably corroborated by an informant, with selective impairment of short-term memory but no substantial interference with daily living activities [4]. MCI lies between normal cognition and dementia, and is a risk factor for dementia. Dementing disorders are characterized by an increasing disability resulting in social and occupational decline.

The objectives of the treatment of dementia are manifold and include the primary prevention of the disease, slowing or arrest of cognitive decline, and improvement or abatement of behavioral symptoms. Data on the prevention of dementia are very limited because prevention studies must be necessarily large and prolonged, with expected high dropout rates. At present there is no treatment that modifies the natural history of the disease or changes its outcome. Potential treatments include drugs that increase the levels of neurotransmitters involved in cognitive functions, protect structurally or functionally damaged neurons, and replace neurons (neuronal regeneration).

Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are the only drugs with some efficacy and a fairly acceptable tolerability profile [5]. However, these drugs tend to improve cognitive functions, activities of daily living, and behavior to a very limited extent and for a limited period of time. Memantine, an NMDA-receptor antagonist, in combination with cholinesterase inhibitors, is thought to have beneficial effects [6]. Ginkgo biloba has also been reported to be effective [7]. In contrast, progress in basic science and molecular biology has fostered new interest in symptomatic treatments and disease-modifying approaches.

The results of RCTs in dementing disorders must be interpreted in the light of methodological limitations, especially concerning the diagnostic criteria, disease stages, and definition and choice of the appropriate outcome. The typical design is a randomized, double-blind, placebo-controlled, parallel-group study comparing change at two primary end points, one of them reflecting the cognitive domain and the other reflecting the functional domain of impairment [8]. The ideal outcome should be easy to measure, and easily collectable at each follow-up over a significant period of time (ideally for several years). These measures should have good reliability, especially considering that many trials are multi-institutional.

Cognitive decline is difficult to quantify with the available instruments. Typical problems are floor and ceiling effects, regression to the mean, learning, and placebo effects. Moreover, the expected changes over a short period are small compared to the possible cognitive range of each scale. More suitable and robust end points include loss of independence, loss of specific daily living functions, and placement in a nursing home. However, these end points require prolonged follow-up and may be influenced by other environmental factors like the presence of an active caregiver, and the economic and social environment. In addition, several prognostic variables must be taken into account. These include, among others, the severity of dementia at admission, the apolipoprotein E genotype, the profile of β-amyloid and tau in the cerebrospinal fluid, and vascular risk factors.

Cognitive functions can be assessed with a battery of tests covering memory, language, constructional abilities, attention/concentration, and psychomotor speed. Remote and recent memory are explored along with recall and recognition for various modalities. Verbal and visuospatial memory are also investigated. The Mini-Mental State Examination (MMSE) [9] is generally used as a screening test for cognitive impairment while the Clinical Dementia Rating (CDR) [10] is used for grading disease severity. The Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) [11] is a comprehensive cognitive scale. However, none of the available instruments can be preferred as being more valid and reliable. Several scales have been proposed to measure the activities of daily living and to assess an overall clinical improvement, but none is preferably used in RCTs. Moreover, these tests have acceptable validity and reliability only in AD.

Depending on the type and course of each dementing disorder and the type of treatment, the duration of an RCT may vary from 6 months to several years. As there are no ideal study designs showing unambiguously a disease-modifying effect of a drug, long-term placebo-controlled studies are needed with periodic measurements of clinical outcomes to establish clinically relevant effects. This procedure, however, is not without problems. An RCT in patients with MCI should be of sufficient length for the primary end point (time to the conversion to dementia) to occur. As patients with MCI are expected to convert to dementia at a 10-15% rate per year [12], a statistically significant, clinically relevant, and sustained treatment effect can be documented only in a 3-year trial. Placebo must be used to detect the effects of treatment on disease progression. However, the study population enrolled in such a trial may have a high dropout rate for lack of compliance or premature mortality. In addition, patients with MCI may have the disease already at baseline, and thus the study is not really designed for prevention of dementia.

One critical issue is the incorporation of biomarkers (e.g. magnetic resonance imaging (MRI), positron emission tomography, cerebrospinal fluid markers) as surrogate end points. Biomarkers could signal the pathophysiology of the dementing condition, thus helping to differentiate disease-modifying from symptomatic effects. However, to be accepted, a biomarker should ideally respond to treatment, predict clinical response, and be correlated to the underlying pathophysiological processes. In this regard, each biomarker should be validated prior to being included in an RCT.

Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder in the elderly. The primary areas of CNS injury are typically the substantia nigra and the locus coeruleus. The disease is characterized by degeneration selective loss of dopaminergic neurons and, to a lesser extent, of other neural cells involving different neurotransmitter systems in different areas of the nervous system [13]. PD causes progressive disability, mostly characterized by motor dysfunction and including dysautonomia (sialorrhea, seborrhea, constipation, micturition disturbances, sexual dysfunction, orthostatic hypotension, hyperhidrosis), sleep and olfactory disturbances, cognitive changes (ranging from loss of executive function, or Lewy-body dementia, to a dementia indistinguishable from AD), and depression. The diagnosis of PD is clinical and requires bradykinesia and tremor, rigidity, and/or postural instability (at least 1 of these) [14]. PD must be differentiated from parkinsonian syndromes (‘atypical’ parkinsonisms) that include progressive supranucleal palsy, multiple system atrophy, and toxic, drug-induced and post-encephalitic parkinsonism [13]. There is neither a known cure nor any recognized method for slowing the ongoing degenerative process.

Currently available therapies include L-DOPA (combined with a peripheral DOPA-decarboxylase inhibitor), dopamine agonists, monoamine oxidase inhibitors, catecholamine-O-methyl transferase inhibitors, and anticholinergics [15]. These treatments are symptomatic and tend to minimize the motor dysfunction of PD through increase of the activity of the nigrostriatal dopamine system, although the overall benefit is partial, and not sustained over the years. In addition, these therapies have disabling and/or dose-limiting adverse effects. Acute adverse effects include nausea and hypotension. Chronic adverse effects include involuntary movements (dyskinesia, dystonia, choreoathetosis), somnolence, psychiatric symptoms (hallucinations, delusions, psychosis), and autonomic side effects. Treatments for the nonmotor disabilities of PD are few, and none are universally effective. In contrast to PD, there are no effective therapies for ‘atypical’ parkinsonisms, although existing antiparkinsonian therapies may provide short-lived partial benefit for a minority of patients. The response to some antiparkinsonian agents, notably those including L-DOPA, can vary dramatically over time. Variation can occur over hours or even minutes during the course of a single dose, and can be further modified by the time of day, number of prior doses, type of concurrent therapies, and timi...