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Alzheimer's Association International Conference (AAIC) · 2024:Poster Tue-17 · Hendrix, Dickson et al.
Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable…
When the sample size a conventional design demands is larger than the trial you can run, a Global Statistical Test lets the clinical-endpoint hypotheses be tested anyway. The paper sets out when GST applies, how it is pre-specified, and how it has been received in review.
11 publications
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2024 · J Clin Pharmacol
Dayley, Caleb · Salt, Andrew · Pick, Christina · Durrant, Abe · Johnson, Sam · Nicodemus-Johnson, Jessie · Dickson, Samuel · Hendrix, Suzanne
To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.
2024 · J. Dement. Alzheimer's Dis
Mallinckrodt, Craig · Hendrix, Suzanne · Dickson, Samuel
Background: The heavily right-skewed data seen in recently reported Alzheimer’s disease (AD) clinical trials influenced treatment contrasts when data were analyzed via the typical mixed-effects model for repeated measures (MMRM). Methods: An MMRM analysis similar to what is commonly used in AD clinical trials was compared versus robust regression (RR) and the non-parametric Hodges–Lehman estimator (HL). Results: Results in simulated data patterned after AD trials showed that imbalance across treatment arms in the number of patients in the extreme right tail (those with rapid disease progression) frequently occurred. Each analysis method controlled Type I error at or below the nominal level. The RR analysis yielded smaller standard errors and more power than MMRM and HL. In data sets with appreciable imbalance in the number of rapid progressing patients, MMRM results favored the treatment arm with fewer rapid progressors. Results from HL showed the same trend but to a lesser degree. Robust regression yielded similar results regardless of the ratio of rapid progressors. Conclusions: Although more research is needed over a wider range of scenarios, it should not be assumed that MMRM is the optimal approach for trials in early Alzheimer’s disease.
2024 · Clin Lung Cancer
Haaland, Benjamin
Introduction/background: Prognostication by performance status (PS) assessment is a fundamental element of treatment decisions and clinical trial design in oncology, but it is limited by subjectivity and potential miscommunication between patient, physician, and family. Activity tracker offers the potential to collect a broad range of patient-generated data to supplement the assessment of PS. Patients and methods: Patients with metastatic NSCLC (mNSCLC) participated in a single institute, prospective, observational feasibility study conducted at Huntsman Cancer Institute. Patients were given a Fitbit® activity tracker, which collects their steps taken, distance moved, heart rate, and activity intensity. At baseline, PS was assessed by physicians and patients, and demographics and clinical data were collected. We defined novel indices of health: Heart rate Activity zone Mismatch (HAM) and excessive Sedentary Heart Rate (eSHR). We used multivariable Cox proportional hazards models adjusted for age, sex, and treatment line to estimate and test the prognostic ability of clinical and fitness metrics on overall survival (OS). Each prognostic model was evaluated using Harrell's concordance index (C-index). Results: Fifty-five patients with mNSCLC were enrolled. The median OS was 10.4 months (95% CI: 7.2, 15.2). PS-physician (HR = 2.0; P < .001) and Fitbit metrics were associated with OS, including daily total steps (1,000-steps) (HR = 0.8; P = .004), HAM (HR = 2; P = .02), eSHR (HR = 0.3; P = .001). The prognostic model that includes PS-physician was associated with the best concordance (C-index = 0.75), followed by daily total distance (C-index = 0.74) and steps (C-index = 0.73) CONCLUSIONS: Tracker-based measures were prognostic of survival in mNSCLC and may be useful as a supplement or alternative to PS in practice and clinical trials.
2024 · Neurology and Therapy
Dickson, Samuel · Mallinckrodt, Craig · Hendrix, Suzanne
Introduction: The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression. Methods: The GENCOMS method relies on robust natural history data and/or placebo arm data from DMT trials. Validated scales that are core to the disease process have been identified, and item level data obtained to standardize the response outcomes from 0 (best possible score) to 1 (worst possible score). A partial least squares regression analysis was conducted with temporal change as the dependent variable and change scores in standardized items as the explanatory variables. The derived model coefficients constitute a weighted sum of items that most effectively measure disease progression. Results: The resultant composite scale was optimized to detect disease progression and can be examined in a range of slow or fast progressing populations. The scale can be used in studies with comparable patient populations as an endpoint optimized to measure disease progression and therefore ideally suited to assess treatment effects in DMTs. Conclusion: The methodology presented here provides a generalizable framework for developing composite scales in the assessment of neurodegenerative disease progression and evaluation of DMT effects. By objectively selecting and weighting items from previously validated measures based solely on their sensitivity to disease progression, this methodology allows for the creation of a more responsive measurement of clinical decline. This heightened sensitivity to clinical decline can be utilized to detect modest yet meaningful treatment effects in the early stages of neurogenerative diseases, when it is optimal to begin a DMT.
2024 · Med
Clinical management and therapeutics development for Alzheimer's disease (AD) have entered a new era, with recent approvals of monoclonal antibody therapies targeting the underlying pathophysiology of the disease and modifying its trajectory. Imaging and fluid biomarkers are becoming increasingly important in the clinical development of AD therapeutics. This review focuses on the evidence of fluid biomarkers from recent amyloid-β-targeting clinical trials, summarizing biomarker data across 12 trials. It further proposes a simple framework to put biomarker guidance in the context of amyloid-pathway-targeted disease modification, delineates factors that impact biomarker data in clinical trials, and highlights knowledge gaps and future directions. Increased knowledge and data on biomarkers in the context of disease progression and disease modification will help to better design future AD trials and guide the clinical management of patients on AD-modifying therapies, bringing us closer to the implementation of precision medicine in AD.
2024 · Alzheimers Dement (N Y)
Hendrix, Suzanne · Nicodemus-Johnson, Jessie · Knowlton, Newman
Introduction: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. Methods: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). Results: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. Discussion: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD.
2024 · J Prev Alzheimers Dis
Dickson, Samuel · Brownlee, Allison · Haaland, Benjamin · Mallinckrodt, Craig · Hendrix, Suzanne
Assessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer's disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach.
2024 · Alzheimer's Association International Conference (AAIC)
Hendrix, Suzanne · O'Keefe, Patrick · Hendrix, Kent · Dickson, Samuel
Background: Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable despite possible victimization by these practices because these sites introduce a negative bias, meaning that effects may be larger than estimated in a clinical trial; however, safety concerns may be underestimated. Ease of simulating Alzheimer's diagnosis documentation (based on clinical or blood markers) and clinical outcome data, coupled with inadequate oversight by Contract Research Organizations (CROs), facilitates deceptive practices. Fraudulent practices at sites and with patients ("professional patients") often go hand-in-hand and flourished during COVID, and must be aggressively addressed in the post-COVID environment. Requiring and scrutinizing PET scans increases the chance of detecting fraud. Alarmingly, sites most prone to deceitful practices include predominantly underrepresented populations, thwarting inclusion efforts. Methods: We reviewed completed and ongoing studies to estimate the percentage of potentially fraudulent sites. We developed medical audit methods, based on extensive AD neurology experience, to identify issues invisible in regulatory audits; traditional rater training, data review, data management and statistical analysis methods fail to identify these issues. We use expected enrollment and true effect size to estimate potential bias and added variability introduced by these sites, and we propose methods for detecting fraud based on clinical and operational data. Results: In studies not requiring PET scans, approximately 10% of sites may be fraudulent, corresponding to a higher proportion of enrolled subjects (~20-50%). These sites can reduce observed effect size by 40% (estimated bias) at best and can completely cancel out a true treatment effect at worst. We estimate variability increases by 35-100%, reducing our ability to observe significance. Algorithms to identify potentially problematic study sites and individuals, and methods for site inspections to investigate issues, are shared confidentially rather than broadly, to prevent sites from circumventing the algorithms. Conclusions: Fraudulent practices at Alzheimer's disease clinical sites have caused serious problems for many companies in this space. AD clinical trials affected by even a minority of fraudulent sites may have underestimated treatment effects. We have developed a toolbox for combating these issues, including best practices for enhanced CRO oversight, incorporation of medical expertise in audits, and identification of problems based on targeted, blinded statistical algorithms, and we freely share it with qualified researchers. The AD community must take a unified aggressive stance against fraudulent practices to safeguard AD research integrity, protect and benefit vulnerable populations, and accelerate development of effective therapeutics.
2024 · Cerebellum
Dickson, Samuel · O'Keefe, Patrick · Hendrix, Suzanne
Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763). PLS regression selected items based on their ability to detect clinical decline, with optimized weights based on the item's degree of progression. Following model validation, SCACOMS was leveraged to examine disease progression and treatment effects in a 48-week SCA clinical trial cohort (NCT03701399). Items from the Clinical Global Impression-Global Improvement Scale (CGI-I), the Friedreich Ataxia Rating Scale (FARS) - functional stage, and the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) were objectively selected with weightings based on their sensitivity to clinical decline. The resulting SCACOMS exhibited improved sensitivity to disease progression and greater treatment effects (compared to the original scales from which they were derived) in a 48-week clinical trial of a novel therapeutic agent. The trial analyses also provided a SCACOMS-derived estimate of the temporal delay in SCA disease progression. SCACOMS is a useful composite measure, effectively capturing disease progression and highlighting treatment effects in patients with SCA. SCACOMS will be a powerful tool in future studies given its sensitivity to clinical decline and ability to detect a meaningful clinical impact of disease-modifying treatments.
2024 · Front Neurol
Nicodemus-Johnson, Jessie · Hendrix, Suzanne
Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.
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