About the Research

This study examined two episodic memory measures – the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Cogstate International Shopping List Test (ISLT) – to compare their clinical and amyloid screen failure rates in early AD trials.

Authors: S. Negash, C. Weber, C. Randolph

Presented at the 11th Clinical Trials on Alzheimer’s Disease (CTAD), Barcelona, Spain (October 2018)

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And as we all know, historically there’s been a high error rate, with mistakes in both administration and scoring of the cognitive scales. This leads to variance that can ultimately doom a trial, particularly disease-modifying trials where the expected treatment effect over shorter trials is expected to be relatively small.  In such cases, error variance has the potential to interfere with signal detection. 

More than ever before, raters need to be carefully trained. We used to teach raters what to do, test them, and then send them on their way to conduct assessments, with no ongoing training. That may have been fine for some short trials, but it will not work for extended CNS trials, especially Alzheimer’s trials. Unfortunately, too many sponsors and CROs still take that approach. Among the consequences: rater drift and inconsistency.

Improving standardization

In a multiyear trial, rater drift is a vital concern. And there’s the issue of consistency across raters. As new raters come in over the course of a long trial, they need to administer and score the same way as all the other raters. In international trials, the risk of variability is greatest, given that raters with widely diverse backgrounds are collecting the outcome measures.¹

To ensure consistency, you must change the way you train.

At WCG MedAvante-ProPhase, we’ve largely shifted our approach to online modules that are live throughout the life of the study. We deliver flexible training based on decades of clinical experience.

In fact, we never stop training. Our eLearning Center, available online 24/7, provides opportunities for self-training and refreshers; this can be particularly useful during long studies.

Perhaps most important, our assessment platform itself is designed to support ongoing training.

Virgil guides the way

Virgil, our electronic clinical outcome assessment tool, includes built-in clinical guidance as well as consistency checks.

The tablet raters use for the assessments gives them access to the industry’s largest library of electronic rating scales and a tightly integrated web portal for real-time data analysis. It’s already being used in trials at more than 900 sites in 30 countries.

We’ve built in pop-up guides–similar to the alerts that pop up on an EHR. Let’s say a rater administering the Clinical Dementia Rating (CDR) enters a score for the Memory domain which is inconsistent with information provided by the informant during the course of the interview.  This will immediately trigger a popup alert that highlights how the score is inconsistent and allow the rater the opportunity to reconsider his or her score.

We also routinely build in central oversight via Independent Review in these long trials.  The Virgil system can be configured to automatically audio-record assessments, allowing our expert calibrated clinicians to review the assessments and provide feedback to site raters on administration and scoring of the assessments.  The algorithms for triggering an Independent Review can be based upon the rater (first assessments administered, or upon elapse of a given amount of time since last review), the visit (key visits like baseline and final visit), or via Clinical Data Analytics (CDA).  The latter trigger can be built upon statistically implausible score change from the prior assessment, internal data inconsistencies, or other data-based anomalies that are likely to be associated with scoring errors

Always learning

Virgil addresses the problem of subjectivity while keeping raters trained. It provides raters with real-time clinical guidance as they administer the assessment. As a result, it can cut site-rater errors by 50 to 85 percent across four common cognitive scales.²

The old way of working with raters simply won’t work for today’s studies. There’s no room for methodological imprecision, especially in AD trials. Time is running out.

References

1. Grill, J.D. et al. Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer’s disease clinical trials. Alzheimers Res. Ther. 7, 39 (2015).
2. Negash S, Böhm P, Steele S, Sorantin P, Randolph C. Virgil Investigative Study Platform Minimizes Scoring Discrepancies to Improve Signal Detection. MedAvante Inc.; Loyola University Medical Center. Poster presentation, 14th Annual Athens/Springfield Symposium on Advances in Alzheimer Therapy, March 2016.

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Over the last few decades, researchers have made tremendous advances in understanding what Alzheimer’s disease does to the brain. That has paved the way for current and future research into therapies that could prevent the disease, or at least delay its onset by a few years.

But although my colleagues and I are optimistic, that doesn’t change the fact that no new AD drug has been approved since 2003. From 2002-2012, drug candidates have had a 99.6 percent failure rate.[i] In some cases, the proposed therapeutic may have been ineffective. But in others, the flaw could be due to the trial execution and/or design.[ii]  The more we learn, the easier it will be to understand that distinction in future trials.

The first few lessons relate to trial design and execution:

Lesson 1: Enrollment often happens too late.

Prevention trials need patients who are pre-symptomatic, or have only the mildest of symptoms. Many Alzheimer’s patients don't get diagnosed until they’re almost past the stage researchers are looking for.

Lesson 2:  Many individuals participating in AD trials don’t even have the disease.

Up to half of people with mild cognitive impairment and a quarter with mild dementia do not have measurable amyloid plaque development–a key AD biomarker.[iii] Many of these individuals nevertheless end up in AD trials, including anti-amyloid ones. This skews results, especially when it comes to placebo decline.

Lesson 3: Old-school rater training won’t work.

The conventional once-and-done approach simply won’t work for AD prevention trials that can run for years. Because the risk of variability is exceptionally high, raters need consistent training/feedback over the life of the trial.

Lesson 4: Paper assessments are obsolete.

A paper-based approach increases the potential for rater and administrative errors. This effect is often compounded by subjectively reported and scored assessments. In fact, research has found the use of paper-based assessments could be an important factor in failed or inconclusive trials.[iv] Electronic clinical outcome assessment (eCOA) tools–not just digital versions of paper COAs–are essential to the AD trials of today and tomorrow. For example, merely replacing a paper scale with a digital one fails to take advantage of the flexibility and sophistication of a fully computerized platform–especially with respect to pop-up support, built-in clinical guidance, consistency checks, etc.

Lesson 5: Biomarkers will transform research.

In April 2018, the National Institute on Aging and the Alzheimer’s Association released a framework in which biomarkers would define the presence of disease for the purposes of research. It will allow researchers to better identify candidates to enroll in clinical trials. It also provides a more accurate way to measure disease progression. Ideally, this means less time wasted, which could speed development and reduce costs. This approach got a tentative green light from the FDA in early 2017 in the form of draft guidance around the use of biomarkers. In early- stage trials, drug developers would no longer have to prove that their therapy met the endpoints of “cognition and function.” Instead, they can use biomarkers as endpoints. It will be possible to get an expedited approval for a compound that was shown to have an impact on a biomarker.

The last three lessons relate more to the therapies themselves.

Lesson 6: Tau continues to be a promising target.

Research will continue to focus on prevention, and it will continue to assess the role of amyloid and Tau proteins. (In fact, we anticipate more anti-tau trials for Alzheimer’s and other neurodegenerative diseases.)

Lesson 7: We expect a verdict on the amyloid hypothesis soon.

It remains an open question right now whether an anti-amyloid strategy is going to work at any stage of disease, but it seems less likely that it will work after the onset of significant dementia.  Several prevention trials are in the works, and we’ll know about the validity of the amyloid hypothesis by the time these all read out. In the meantime, researchers will focus more on tau. One possibility is that there’s some sort of pathological interface between amyloid and tau and that amyloid may mediate tau-related pathology in some way.

Lesson 8: Monotherapy may not be the way to go.

It’s possible the key to slowing, stopping or preventing AD lies in combination therapies instead of monotherapies. We just don’t know yet. But we soon may, as the use of biomarkers increases.

Moving forward

The science is advancing quickly. Pharmaceutical companies and biopharma organizations need a partner who grasps the particulars of Alzheimer’s clinical trials.

WCG is running–or has run–more than 30 of them, at every stage of the disease. Currently, we’re involved in over 2,000 sites around the world actively researching potential therapies. Our system is established, our raters are the best trained in the industry, and our leadership includes the leading clinicians and researchers in this area.

The post Homing In On a Moving Target: Meeting the Challenges of Alzheimer’s Disease Research appeared first on WCG.

Background

The Clinical Dementia Rating scale (CDR) is a subjectively rated clinician-reported outcome measure, used as a sole primary endpoint in clinical trials of early symptomatic Alzheimer’s disease (AD).

The CDR is also a key secondary endpoint that contributes to diagnostic classification in prevention trials for time-to event analyses, and also used as a co- primary endpoint in some trials of mild to moderate dementia due to AD1 .

Scoring the CDR can be challenging, particularly in mild disease; rater administration and scoring errors are common.

The goal of this study was to identify a CDR quality metric, based upon internal patterns of domain scores that could be used to identify atypical patterns that might be indicative of scoring errors.

The post Identifying Elevated Rates of CDR Scoring Errors appeared first on WCG.

Abstract 

Objectives: The aim of this study was to evaluate the reliability and validity of three computerized neurocognitive assessment tools (CNTs; i.e., ANAM, DANA, and ImPACT) for assessing mild traumatic brain injury (mTBI) in patients recruited through a level I trauma center emergency department (ED). Methods: mTBI (n = 94) and matched trauma control (n = 80) subjects recruited from a level I trauma center emergency department completed symptom and neurocognitive assessments within 72 hr of injury and at 15 and 45 days post-injury. Concussion symptoms were also assessed via phone at 8 days post-injury. Results: CNTs did not differentiate between groups at any time point (e.g., M 72-hr Cohen’s d = −.16, .02, and .00 for ANAM, DANA, and ImPACT, respectively; negative values reflect greater impairment in the mTBI group). Roughly a quarter of stability coefficients were over .70 across measures and test–retest intervals in controls. In contrast, concussion symptom score differentiated mTBI vs. control groups acutely), with this effect size diminished over time (72-hr and day 8, 15, and 45 Cohen’s d = −.78, −.60, −.49, and −.35, respectively).

Conclusions: The CNTs evaluated, developed and widely used to assess sport-related concussion, did not yield significant differences between patients with mTBI versus other injuries. Symptom scores better differentiated groups than CNTs, with effect sizes weaker than those reported in sport-related concussion studies. Nonspecific injury factors, and other characteristics common in ED settings, likely affect CNT performance across trauma patients as a whole and thereby diminish the validity of CNTs for assessing mTBI in this patient population. (JINS, 2017, 23, 1–11)

The post Prospective, Head-to-Head Study of Three Computerized Neurocognitive Assessment Tools Part 2: Utility for Assessment of Mild Traumatic Brain appeared first on WCG.

The post Is cognitive decline measurable in preclinical Alzheimer’s disease? appeared first on WCG.

Abstract

The Horizon 2020/IMI European Prevention of Alzheimer’s Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer’s disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer’s disease.

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Abstract

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer’s disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist.

How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer’s Association’s Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials. High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses. 

The post Multiple Comorbid Neuropathologies in the Setting of Alzheimer’s Disease Neuropathology and Implications for Drug Development appeared first on WCG.