Disease-modifying Trials Research Articles

Advances in molecular imaging for the diagnosis of dementia

There is an urgent need for early diagnosis and treatment of dementia to ease caregiver burden and medical costs associated with the increasing number of affected patients. Molecular imaging with target-specific ligands is contributing to the early diagnosis of dementia and the evaluation of anti-dementia therapy. This article reviews recent advances in the molecular imaging field applied to dementia. To illustrate the utility of molecular imaging in the clinical management of dementia, results from recently published papers using new imaging probes are compared with those from conventional imaging strategies. The recent development of β-sheet binding agents including FDDNP, PIB, SB-13, BF-227 and BAY94-9172 enables the non-invasive detection of amyloid deposition in the brain. These agents would be useful for the early and accurate diagnosis of Alzheimer's disease, patient selection for disease-modifying therapeutic trials and monitoring the effect of anti-amyloid therapy. Also, monitoring neurotransmitter function contributes to the differential diagnosis of dementia and refinement of treatment protocols. New targets for molecular imaging are focusing on protein misfolding diseases associated with the neurotoxic deposition of aggregated tau, α-synuclein and prion proteins.

Biomarkers for Alzheimer's disease trials--biomarkers for what? A discussion paper.

The search for biomarkers has become an increasingly active strand of research in recent years. This trend, with the underlying concept of individualised or personalised medicine, applies as much to Alzheimer’s disease (AD) research as it does to others such as oncology or cardiovascular medicine where biomarkers are in active clinical use. A search of PubMed shows an increasingly rapid rise in the numbers of publications in the decade since the publication of the NIA/AA consensus report on AD biomarkers (1) (figure 1). The success in this work, the identification of CSF and imaging markers in particular, has been widely reviewed elsewhere; indeed approximately one third of all publications in the field identified with the above literature search strategy appear to be reviews – a sign perhaps of a research field showing some success but even greater promise. This article does not attempt to review the field of biomarkers in AD but to consider only the use of biomarkers in clinical trials and, specifically, to suggest some criteria for biomarkers to be used in disease modification trials.

Interpreting biomarker data in therapeutic trials.

Alzheimer’s disease (AD) is not directly observable; definite diagnosis requires histopathological investigation post-mortem. Clinical diagnosis must necessarily utilize biomarkers, characteristics that can be objectively measured as indicators of the neurobiology. Neuropsychological assessment can be viewed as a form of biomarker measurement, with the advantage of face validity, as cognitive impairment represents the primary symptom of the disease. Cognitive testing is useful in diagnosis and in monitoring response to therapy, but as an indirect measure it is not in itself sufficient for either purpose. Clinical assessment must be included with neuropsychological testing for reasonably accurate diagnosis or assessment of the impact of therapeutic intervention. Combining cognitive assessment with clinical assessment has been sufficient for the development of symptomatic treatments that directly improve cognition in the short-term. But many factors confound cognitive and clinical assessments, including heterogeneity of disease symptoms, medical comorbidity, concomitant medications, variable quality and experience of raters; the impact of these factors is generally aggravated in long trials involving many performance sites. Therefore, development of disease-modifying treatments, requiring trials with many subjects and long observation periods, is complicated by variance in cognitive and clinical assessments. Biomarker assessments in blood, cerebrospinal fluid or involving neuroimaging may be critical to successful diseasemodifying trials. Such biomarkers can directly reflect pharmacodynamic effects (eg, measurement of cerebrospinal fluid abeta peptide levels in response to secretase inhibitors), support proposed mechanisms (eg, measurement of plasma abeta elevation to indicate sequestration induced by passive immunotherapy), or suggest an impact of treatment on brain structure (with MRI volumetric analysis) or histopathology (with amyloid neuroimaging). Further, baseline biomarkers measurements can be utilized as covariates in analyses, reducing unexplained variance and thereby increasing the power to demonstrate treatment effects. Potential Pitfalls

Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of Tau-aggregation inhibitor therapy.

Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of Tau-aggregation inhibitor therapy.

“Disease-modification” trials in Parkinson disease: Target populations, endpoints and study design

"Neuroprotective" compounds that block dopamine cell death are expected to slow the progression of the neurologic symptoms of Parkinson disease (PD) and therefore "modify" the disease course. However, presently, no fully satisfying efficacy "disease-modification" study design exists, and no drug has yet been approved for that indication. This is inherent to the slow progression of PD with respect to the limited time for patient follow-up and exposure to placebo, the modest effects of investigated drugs, and the confounding effects of symptomatic medications used to treat patients with PD. Disease-modification trials assessing drug efficacy on PD progression are currently prospective, randomized, parallel-group, placebo-controlled, long-term (1-3 year) studies. Untreated patients with early PD represent the main target population because more neurons remain for protection, PD may progress faster, and symptomatic medications are not needed at this stage. "Long lasting" prevention/postponement of disability is a relevant objective for such trials and two main types of outcome and analysis are proposed: slopes analysis of cardinal clinical feature progression (Unified PD Rating Scale, UPDRS) or survival curve analysis of "time to emergence" of clinically relevant milestones (time to dopaminergic therapy, Hoehn and Yahr stage III, etc.). The use of biomarkers remains investigational. Wash-out and delayed-start designs have been proposed to disentangle symptomatic and neuroprotective mechanisms, although this clarification might not be so important practically, as long as the effect on disability is large and long-lasting. To observe clinically relevant changes, several years of follow-up is required, and controlled, randomized, pragmatic trials should be considered when establishing clinical development plans.

Clinical measures of progression in Parkinson's disease

Despite all recent advances in symptomatic therapy Parkinson's disease (PD) continues to be a relentlessly progressive neurodegenerative disorder. Therefore therapies that will slow or hold disease progression are a major medical unmet need in PD. Clinical measures of disease progression that have been used in disease modification trials so far have focused on indices of progression of cardinal motor features like bradykinesia, rigidity, and tremor as captured by the UPDRS and the emerging need for effective dopaminergic symptomatic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites in the brain or peripheral autonomic nervous system contribute to poorly levodopa responsive motor symptoms like postural instability, freezing and falls or nonmotor symptoms. In addition treatment-induced motor complications also impact on PD disability. Although it is widely accepted that clinical progression of PD is multidimensional and in addition includes effects of aging, there is no consensus how to best implement more clinically meaningful endpoints for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers for disease progression that would faithfully reflect advancing neurodegeneration and resulted clinical disability in PD and that could be used in shorter term clinical trials testing putative disease modifying agents.

Applications of neuroimaging to disease-modification trials in Alzheimer's disease.

Critical to development of new therapies for Alzheimer’s disease (AD) is the ability to detect clinical or pathological change over time. Clinical outcome measures typically used in therapeutic trials have unfortunately proven to be relatively variable and somewhat insensitive to change in this slowly progressive disease. For this reason, development of surrogate biomarkers that identify significant disease-associated brain changes are necessary to expedite treatment development in AD. Since AD pathology is present in the brain many years prior to clinical manifestation, ideally we want to develop biomarkers of disease that identify abnormal brain structure or function even prior to cognitive decline. Magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, new amyloid imaging techniques, and spinal fluid markers of AD all have great potential to provide surrogate endpoint measures for AD pathology. The Alzheimer’s disease neuroimaging initiative (ADNI) was developed for the distinct purpose of evaluating surrogate biomarkers for drug development in AD. Recent evidence from ADNI demonstrates that imaging may provide more sensitive, and earlier, measures of disease progression than traditional clinical measures for powering clinical drug trials in Alzheimer's disease. This review discusses recently presented data from the ADNI dataset, and the importance of imaging in the future of drug development in AD.

Disease Modifying Trials in Alzheimer's Disease: Perspectives for the Future

Disease modifying trials are becoming increasingly common in the field of Alzheimer's disease (AD) as the search for a treatment able to slow the progression of this disease continues. In this paper, we briefly discuss the methodological considerations for disease modifying trials that were addressed during three recent international task force meetings involving specialists in the field of AD trials. Topics covered included study design, the identification of appropriate outcomes, the use of biomarkers, and the identification of suitable study populations. We also provide an update on recent disease modifying trials which have enabled us to gain experience in the use of biomarkers and have helped to define suitable outcomes, and consider how they can help us to shape future perspectives for disease modifying trials.

S2-03-04: Role of aminopeptidase NPPS in tauopathy

Abstract not available.

Endpoints for trials in Alzheimer's disease: a European task force consensus

Harmful consequences in health status caused by disease are referred to as outcomes, and in clinical studies the measures of these outcomes are called endpoints. A major challenge when deciding on endpoints is to represent the outcomes of interest accurately, and the accuracy of such representation is assessed through validation. Complex diseases like Alzheimer's disease have many different and interdependent outcomes. We present a consensus for endpoints to be used in clinical trials in Alzheimer's disease, agreed by a European task force under the auspices of the European Alzheimer Disease Consortium. We suggest suitable endpoints for primary and secondary prevention trials, for symptomatic and disease-modifying trials in very early, mild, and moderate Alzheimer's disease, and for trials in severe Alzheimer's disease. A clear and consensual definition of endpoints is crucial for the success of further clinical trials in the field and will allow comparison of data across studies.

Progress in Neurotherapeutics and Neuropsychopharmacology 2008

There has been continuous progress in neurotherapeutics and neuropsychopharmacology in the past year. Notable are the reports of successful preliminary disease-modifying trials in Niemann-Pick disease and Friedreich's ataxia. Progress also has been made in treatment of migraine, stroke, epilepsy, multiple sclerosis, traumatic brain injury, and pain. Biomarkers are increasingly used to establish proof of pharmacology including measures of cerebrospinal fluid constituents and brain changes on magnetic resonance imaging. There is an increasing diversity of patient populations participating in clinical trials, including pediatric migraine and traumatic brain injury.

Plasma neurofilament heavy chain levels in Huntington's disease

There is a need for biomarkers of onset and progression in Huntington's disease (HD), as current outcome measures lack the reliability to enable the efficient conduct of disease-modifying trials. Neurofilament heavy chain (NfH) is a neuron-specific protein for the neuro-axonal compartment that has been proposed as a marker for axonal injury, degeneration and loss and its clinical use as a biomarker has been suggested in several neurodegenerative diseases. We used an enzyme-linked immunosorbent assay to quantify NfH levels in plasma in control subjects, premanifest HD mutation carriers and subjects with early and moderate manifest HD. We found no correlation between plasma NfH level and disease stage, or calculated parameters based on CAG repeat length, the major determinant of disease course in HD, and no evidence that NfH may be a predictor of disease onset. We conclude that plasma NfH concentration is not a useful biomarker of onset or progression in HD.

New radiographic-based surrogate outcome measures for osteoarthritis of the knee

Objective Minimum joint space width (mJSW) between the femoral condyle and tibial plateau is currently the principal radiographic outcome measure for knee osteoarthritis (OA). While mJSW measurement has been proven effective, there is a need for quantitative measures with greater sensitivity to OA so studies of disease modifying trials can be performed more quickly and with fewer subjects. Also, mJSW is a single outcome measure that does not reflect all disease changes. Here we present a study of new radiograph-based outcome measures to quantify OA progression. Design Our goal is made possible by a software algorithm that delineates both the edge of the tibial plateau and the femoral condyle on digitized knee radiographs. We also developed a new coordinate system based on anatomical landmarks to facilitate measurement of the outcome measures. We studied measurements of joint space width (JSW) and average JSW at fixed locations along the joint interface. The outcome measures were tested using duplicate acquisitions made from 16 OA and 18 normal knees. Reproducibility was quantified by the root–mean square standard deviation and the coefficient of variation. Results We found that the reproducibility for all outcome measures was better than or similar to that for mJSW. Despite a slightly higher reproducibility error for some new outcome measures compared to mJSW, they are potentially valuable since they reflect independent disease changes. Conclusion We have demonstrated new reproducible radiographic outcome measures to quantify OA progression with the potential to be an improvement over standard minimum joint space width. Copyright 2003 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.

Plain radiography in the evaluation of knee osteoarthritis.

The prospects for results of controlled studies of disease-modifying osteoarthritis drugs in humans have fostered interest in radiographic methods to detect early cartilage damage and to assess progressive cartilage changes in osteoarthritis of the knee. We summarize here the extent to which technical factors in plain knee radiography-ie, the degree of knee flexion, misalignment of the x-ray beam, magnification of the radiographic image of the joint-and mensural procedures can impact the reproducibility of quantitative measurements of tibiofemoral joint space width, the surrogate for thickness of articular cartilage. Failure to standardize crucial elements of conventional knee radiography and to computerize measurement of tibiofemoral joint space width will introduce significant (and probably insurmountable) error variation into radiographic outcome data. The level of precision achievable with fluoroscopically-assisted flexion of the knee and rotation of the foot with computerized, magnification-corrected measurement of joint space width greatly improves the feasibility of disease-modifying osteoarthritis drug trials as they relate to sample size and duration of treatment necessary to detect an effect from disease-modifying osteoarthritis drugs.