Over 200 publications, including the composite endpoints regulators now recognize. We publish our methodology in the open so reviewers meet it before your submission does.
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.
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2010 · Alzheimer's & Dementia
Background: In patients with Alzheimer's disease (AD), a declining ability to communicate has been associated with increased caregiver stress. In a previously reported, randomized trial in moderate AD (NCT00469456), memantine was superior to placebo at improving functional communication, as recognized by caregivers. Here we focus on patients from that trial who experienced a worsening on two measures of functional communication: the primary study endpoint, an assessment of patients using the Functional Linguistic Communication Inventory (FLCI), and the secondary study endpoint, an assessment of caregivers using the combined Social Communication and Communication of Basic Needs subscales of the American Speech-Language-Hearing Association - Functional Assessment of Communication Skills of Adults scale (ASHA-FACS). Methods: Native English-speaking outpatients with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized study of memantine (20 mg/day; ITT n = 133) versus placebo (ITT n = 124). Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. In this post hoc analysis (LOCF), we selected patients whose changes on the FLCI or the ASHA-FACS subscales indicated any worsening (<0, both measures), greater-than-mild worsening (decline of more than 0.5 standard deviations: FLCI, <-3; ASHA-FACS, <-10), or greater-than-moderate worsening (decline of more than 1.0 standard deviation: FLCI, <-6; ASHA-FACS, <-20). We then used Generalized Estimating Equations to compare treatment groups in terms of proportions of patients who experienced each degree of worsening at endpoint and overall (i.e., throughout the trial). Results: On the FLCI, no significant difference was observed between memantine and placebo in the proportion of patients who experienced any decline (endpoint and overall); however, a significantly higher percentage of patients in the placebo group experienced greater-than-mild worsening at endpoint (P = 0.032) and overall (P = 0.013) and greater-than-moderate worsening at endpoint (P = 0.039) but not overall (P = 0.081). On the ASHA-FACS, significantly more caregivers of patients taking placebo relative to memantine reported any worsening overall (P = 0.013) but not at endpoint (P = 0.079); significantly greater-than-mild worsening at endpoint (P = 0.012) and overall (P = 0.018), and significantly greater-than-moderate worsening at endpoint (P = 0.011), though not overall (P = 0.133). Conclusions: Memantine treatment of patients with moderate AD may be associated with a prevention of worsening in functional communication.
2010 · Alzheimer's & Dementia
Background: Patients with Alzheimer's disease (AD) experience a decline in language and communication skills, which contributes significantly to caregiver stress. Memantine is an NMDA receptor antagonist approved for the treatment of moderate to severe AD. We previously reported the results of a randomized trial (MEM-MD-71; NCT00469456), which demonstrated that memantine was superior to placebo in improving functional communication in patients with moderate AD, as recognized by caregivers. This report focuses on global clinical status in patients from that trial. Methods: Native English-speaking outpatients with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized study of memantine (20 mg/day; ITT n = 133) versus placebo (ITT n = 124). Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. The primary and secondary measures were baseline-to-endpoint score changes on the FLCI and the Social Communication/Communication of Basic Needs subscales of the ASHA-FACS, which are, respectively, patient- and caregiver-based instruments designed for the assessment of functional communication abilities. An additional outcome measure was patients' global clinical status, assessed using the 7-point Clinician's Global Impression of Change (CGI-C) scale. The distributions of CGI-C scores (OC and LOCF) were compared between groups using a Cochran-Mantel-Haenszel (CMH) test. Post hoc analyses of the proportions of patients (OC and LOCF) who showed any improvement (CGI-C <4) at Week 12 and overall (i.e., throughout the trial) were performed using Generalized Estimating Equations. Results: CGI-C scores at study endpoint (Week 12; Mean ± SD) indicate a significantly better global clinical status of memantine-treated patients, compared to their placebo-treated counterparts (3.8 ± 1.1 vs. 4.0 ± 1.1, P = 0.03; both OC and LOCF). In addition, memantine treatment was associated with a greater proportion of patients who showed an overall improvement at Week 12 (39.1% vs. 28.6%, P = 0.07; OC and 39.1% vs. 28.2%, P = 0.06; LOCF) and overall (P = 0.045; OC and P = 0.04; LOCF). Conclusions: Memantine treatment of patients with moderate AD is associated with an improvement in patients' global clinical status.
2010 · The American Journal of Human Genetics
2010 · European Neuropsychopharmacology
2010 · European Neuropsychopharmacology
2009 · Dissertation
Abstract: In recent years population-based association studies have been advocated as the most powerful method of discovering genetic loci that are associated with heritable traits, particularly for complex traits that are likely caused by a variety of factors including environmental effects and multiple genetic loci. Genome-wide association studies (GWAS) have already yielded a large number of such associations, but there is growing concern that the results of these studies are not explaining as much genetic variation as they were expected to. Chapter 2 discusses tagging and imputation to leverage the information available on commercial genotyping chips to make inferences about variants found in large reference samples such as those made available by the International HapMap Consortium. Transferability of multi-marker tagging is assessed. Tagging and imputation are compared, and a method of using tagging to select a reduced tag set to be used for imputation. Chapter 3 details how multiple low frequency causal variants can create synthetic associations among more common variants and may be responsible for many of the genome-wide associations that have already been observed. Examples of synthetic associations are demonstrated in congenital deafness and sickle-cell anemia. Chapter 4 examines issues related to combining samples of diverse genetic ancestry for analysis in genetic association studies. Through simulation it is shown that type I error can be controlled and power increased using statistical methods to account for differences in populations.
2009 · Dissertation
Abstract: Recruitment for clinical trials is undergoing a major transition, from trial centers concentrated in North America and Western Europe to a much greater emphasis on Eastern Europe, South and East Asia, and Latin America. This shift challenges traditional approaches to genetic association studies, in which studies have been designed around populations of relatively common ancestry. There is particular concern about the potential impact of genetic substructure, stratification and heterogeneity on the analysis of diverse samples. Although methods such as those implemented in STRUCTURE and EIGENSTRAT have been developed to assess and address the problems arising from the analysis of samples containing individuals from multiple populations, we have an insufficient understanding of how population-dependent prevalence, allele frequency, penetrance, and LD affect study type I error and power. Through simulation we explore the effects of heterogeneity in these population parameters on the analysis with a variety of statistical models. We find that type 1 error can be controlled when combining samples. Methods using combined samples outperform methods that rely on analyzing samples separately in ~70% of the conditions considered. The models with the highest overall power were those that assumed a main effect for population with no difference in genetic effect between populations. We conclude that the same information that has been used to exclude data to minimize diversity would be better employed as a statistical covariate in an inclusive analysis.
2009 · Dissertation
Abstract: Tagging and imputation have been developed to make inferences about unmeasured genetic variants. While these methods attempt to address the same problem, their ability to make these inferences has never been directly compared. We compare the efficiency of the inference of tagging using pairwise and multi-marker tags and imputation. Multi-marker tagging is shown to transfer well from a reference population to genetically similar populations in European and African samples, though pairwise tags maintain their predictive power better than multi-marker tags in independent samples. Imputation makes more accurate inferences than tagging, especially compared to multi-marker tags. Imputation is less efficient when imputing SNPs with no tags than for imputing SNPs that have tags, so a method is proposed to use tagging to select a tag set for imputation using lower thresholds and impute the remaining SNPs with this tag set. This method is shown to produce accurate results with fewer SNPs than traditional tag selection methods.
2009 · Alzheimer's & Dementia
Background: Recently, there has been substantial interest in establishing methods for identifying a disease modifying therapy for Alzheimer's disease. The concept of Disease Modification has been approached in many different ways including cross-over study designs (randomized withdrawal and staggered start), use of biomarkers or imaging outcomes, measuring clinically relevant milestones, comparing slopes of decline and comparing adjusted slopes (Natural History Staggered Start analysis - NHSS). These methods are able to distinguish between different patterns of clinical response. Methods: A definition of Disease Modification is proposed that defines a substantially different pattern of clinical response than that of a symptomatic therapy. Additional definitions are proposed to separate out long term and short term symptomatic responses, and permanent and temporary disease modification effects. Clinical approaches are discussed in the context of supporting these distinct types of mechanisms. Results: The Randomized Withdrawal and Staggered Start designs can separate between disease modifying effects and symptomatic effects. The Natural History Staggered Start analysis can also make this distinction without the difficulties of a two-phase study such as: the potential bias and loss of power associated with a high dropout rate, ethical concerns related to removing a potentially efficacious treatment and the long treatment duration required for these two phase studies. Unadjusted slopes analysis and use of clinically relevant milestones can identify long lasting effects without distinguishing between disease modification and symptomatic effects. Use of biomarkers and imaging outcomes can detect effects on the underlying disease process, but will need additional validation in order to demonstrate that these effects are due to disease modification. Conclusions: The pathological process of Alzheimer's disease is not understood well enough to be directly measurable with biomarkers or imaging outcomes, and is not tied to clinical outcomes except through the symptomatology. In this setting, demonstration of disease modification should rely on clinical evidence with support from several sources including: pre-clinical data supporting a disease modifying mechanism of action, biomarkers connecting that mechanism to the clinical efficacy, and imaging outcomes supporting a structural change consistent with modification of the underlying disease.
2009 · The journal of nutrition, health & aging
2008 · Alzheimer's & Dementia
Background: Tarenflurbil is a Selective Aβ42-Lowering Agent (SALA) that modulates γ-secretase activity to preferentially reduce production of Aβ42 in vivo and in vitro. Evidence for potential benefit of tarenflurbil 800 mg bid in subjects with mild AD was recently observed in a randomized, double-blind Phase 2 trial of up to 24 months of treatment. Methods: A target of 1600 subjects with mild AD (MMSE score 20–26) were to be randomized (1:1) to receive tarenflurbil 800 mg bid or placebo for 18 months. Randomization was stratified according to stable use/nonuse of acetylcholinesterase inhibitors (AChEIs) and/or memantine. The co-primary efficacy outcomes are the rate of change (slope) in ADAS-cog and the ADCS-ADL, with assessments conducted every 3 months. The secondary outcome is the CDR-sb, with additional exploratory outcomes including the NPI, Quality of Life-AD, and Caregiver Burden Inventory. ECGs are obtained every 3 months, with adverse events monitored throughout the study. Plasma samples are collected every 3 months for pharmacokinetic and exploratory biomarker analyses. Results: This trial enrolled 1684 subjects at 133 sites in the United States. The last patient visit occured in March 2008, with database lock occuring in June of 2008. At enrollment, 33% of subjects were using AChEIs alone (stable for ≥ 6 months), 6% of subjects were using memantine alone (stable for ≥ 3 months), 41% of subjects were using both AChE is and memantine and 19% of subjects were taking no AD therapy. A second Phase 3 trial of similar design, fully enrolled with 840 subjects, is ongoing in the US, Canada and Europe and is expected to be completed in the clinic in October of 2008. Conclusions: This Phase 3 protocol was developed based on Phase 2 trial results. It is powered to evaluate the efficacy of tarenflurbil with respect to the primary outcomes, and to examine its effect both as monotherapy and as add-on therapy with currently marketed AD medications.
2008 · Patent
Abstract: The invention relates to the treatment of psychiatric disorders.
2007 · Patent
Abstract: In general, the invention relates to a pharmaceutical dose having R-flurbiprofen as the active ingredient that upon oral administration of a single dose to a fasting subject provides a Cmax of about 30-95 µg per mL. When the dose is administered to an individual having mild-to-moderate Alzheimer's disease (or desiring protection against Alzheimer's disease) twice daily for at least 4 months according to the described guidelines, an improvement or lessening in decline of cognitive function as characterized by cognition tests is observed in the patient. The composition of the invention is formulated with one or more pharmaceutically acceptable excipients, salts or carriers.
2007 · Alzheimer Disease & Associated Disorders
Abstract: To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (Abeta42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600 mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of Abeta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid Abeta42 levels and no significant differences in changes of plasma Abeta42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower Abeta42 plasma levels (P=0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma Abeta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.
2007 · European Journal of Neurology
Background: Tarenflurbil is a Selective Ab42-Lowering Agent (SALA) that lowers brain levels of Ab42 in a mouse model of AD and chronic dosing in this model prevents defects in learning and memory. These data and the Phase-2 study indicating sustained benefit in activities of daily living, global function and cognition in mild AD patients, suggest the potential for tarenflurbil to have disease-modifying properties. Methods: This was a placebo-controlled, 1-year study evaluating tarenflurbil in 207 patients with mild-to-moderate AD. At randomization, 94% of subjects were on stable acetylcholinesterase inhibitor therapy. An exploratory post-hoc analysis was performed which compared time to adverse psychiatric events between treatment groups. Results: In subjects with mild AD (MMSE 20–26) was a significant delay in time to clinically significant adverse psychiatric events, 800 mg BID compared to placebo (p=0.011). Among 35% of the placebo group who had an event, the median time was approximately 106 days. In the 800 mg BID group, the median time to event was greater than 333 days with only 14% of this group having an event. The most common psychiatric events reported in the placebo group were agitation, aggression, confusional state and depression.
2007 · American Journal of Orthopsychiatry
Abstract: The violent and peaceful behaviors of 115 children who had or had not witnessed domestic violence were measured in five types of simulated conflict. Witnesses did not differ from nonwitnesses in conflicts involving limited resources, jealousy over possessions, or intimidation; witnesses were significantly more violent in conflicts involving aggression and exclusion. The most violent responses were found among abusers' sons who had been excluded by peers.
2006 · Presented as a poster exhibit at the 10th International Conference on Alzheimer's Disease and Related Disorders, Madrid, Spain
2006 · Alzheimer's & Dementia
Background: MPC–7869 (R–flurbiprofen) is a Selective Aβ42–Lowering Agent (SALA). In a mouse model of AD (Tg2576), MPC–7869 lowers brain levels of Aβ42 and chronic dosing in this model reduces brain amyloid pathology and prevents defects in learning and memory. These data suggest a potential for MPC–7869 to have disease–modifying properties. Objective(s): This study evaluated the efficacy and safety of treatment with MPC–7869 for 12 months in subjects with mild–to–moderate AD, and includes data from a 1–year follow–on study. Methods: This was a placebo–controlled, double–blind, 1–year trial evaluating 400 mg BID and 800 mg BID of MPC–7869 in 207 patients with mild–to–moderate AD (MMSE 15–26, with an average MMSE score of 21). The mean age of the subjects at baseline was 75 years and 94% of subjects were on stable acetylcholinesterase inhibitor therapy. Primary outcomes included measures of cognition (ADAS–cog), activities of daily living (ADCS–ADL), and global function (CDR–sb). A population pharmacokinetic analysis was also performed. At the end of this study, over 80% of eligible patients were enrolled into a 1–year follow–on treatment study in which placebo patients were randomized into one of the two treatment groups and treated patients continued their stable dose. Treatment groups remained blinded to patient/investigator. Results: A prespecified interaction analysis revealed that mild and moderate AD patients responded differently to MPC–7869 (P= 0.03). In mild AD patients (MMSE 20–26) taking the 800–mg BID dose, statistically significant benefit was observed at 12 months in activities of daily living with a treatment effect size of d=0.44 (P= 0.033) and global function with a treatment effect size of d=0.42 (P= 0.042) with a positive trend observed in cognition. In addition, there was a significant plasma drug concentration to response relationship (ADCS–ADL, P= 0.037 and CDR–sb, P= 0.019). No benefit was observed in moderate AD patients. MPC–7869 was well tolerated and patients taking the 800–mg BID dose continued to show benefit in the 1–year follow–on study. Conclusions: MPC–7869 has an attractive therapeutic and safety profile in patients with mild AD. This study justifies larger–scale confirmatory trials of MPC–7869 as an amyloid–based intervention strategy for AD treatment.
2005 · Alzheimer's & Dementia
Background: Several epidemiological studies have suggested that longer-term use of NSAIDs may reduce the risk of developing Alzheimer's disease (AD). Although there were encouraging results from some earlier studies, more recent longer-term, larger, placebo-controlled clinical trials utilising drugs with an anti-inflammatory action have produced disappointing outcomes. Re-analysis of the epidemiological data has shown that the protective effect is limited to a subgroup of NSAIDs, including flurbiprofen, which have Aβ-42 lowering properties and which were not used in the previous longer-term placebo-controlled trials. Flurizan (MPC-7869 (R)-flurbiprofen) is a single enantiomer of flurbiprofen, which has been shown to lower brain levels of Aβ-42 in a mouse model of AD (Tg2576), with some evidence of an effect on learning and memory. There is little risk of gastric toxicity because of a lack of anti-COX activity, and the compound has been shown to be safe and well tolerated in healthy older volunteers (55-80yrs) at doses of up to 1600mg per day when administered for 21 days in a phase I study. It is therefore an exciting potential disease modifying treatment for AD. Objective(s): This presentation will provide efficacy and safety data from a clinical trial of Flurizan, which to our knowledge will be the first multi-centre, placebo-controlled, double-blind clinical study of a selective Aβ-42 lowering agent in patients with mild to moderate Alzheimer's disease. Methods: This is a one-year trial evaluating both 400mg BID and 800mg BID of (R)-flurbiprofen per day, in 210 patients (50% female) with mild to moderate AD (MMSE 15-26). It employed the ADAS-cog, ADCS-ADL, CDR-sb, CIBIC plus, NPI and MMSE as outcome measures. At baseline the mean age of the subjects was 75 years with an average MMSE score 21 and an average standard ADAS-cog score 23. Of the patients enrolled in the trial, 94 per cent were also taking stable doses of cholinesterase inhibitors. Concomitant treatment with memantine was not allowed. Conclusions: The study completes in March 2005, and the cognitive, functional, global and behavioural outcomes will be presented, together with the safety data.
2005 · Cereal Chemistry
Abstract: Staling over a 120-hr period was compared in a gluten-free rice bread, a low-protein starch bread, and two gluten-containing breads (standard wheat and added-protein wheat) using quantitative descriptive analysis (QDA), critical stress values obtained by mechanical compression testing, and scanning electron microscopy (SEM). The gluten-free rice bread had the highest QDA scores for both moistness and overall freshness, whereas the low-protein starch bread had the lowest scores for both attributes. Differences in critical stress values over the 120-hr period demonstrated that the gluten-free rice bread had the greatest resistance to mechanical collapse, indicating the least structural damage, whereas the low-protein starch bread had the least resistance to mechanical collapse. Both wheat breads had QDA moistness and freshness scores, and critical stress values that ranged between the gluten-free rice and low-protein starch breads. SEM showed the formulation containing rice, egg and milk proteins, xanthan gum, and hydroxypropylmethylcellulose created a bicontinuous matrix with starch fragments, similar to gluten.
2005 · Encyclopedia of statistics in behavioral science
Brown, Bruce · Hendrix, Suzanne
2003 · Journal of Emotional Abuse
Abstract: This research explored whether witnessing spouse abuse influences children's use of violent and peaceful behavior in conflicts with peers. Sixty-two child witnesses were compared with 53 non-witnesses across five types of childhood conflicts: limited resources, exclusion, aggression, intimidation, and jealousy. Each conflict was presented in two formats: (1) hypothetical conflicts, and (2) simulated conflict situations. For both, most children, and particularly non-witness males, were consistently peaceful. However, male witnesses were inconsistent and violent in both conflict formats. Female witnesses proposed peaceful strategies in hypothetical conflicts, but were inconsistent and violent in simulated conflicts. Female non-witnesses were consistent and peaceful in simulated conflicts, but were inconsistent and more violent in hypothetical conflicts. Group differences wereprimarily due to subsets of children.
2003 · Patent
Brown, Bruce · Hendrix, Kent · Hendrix, Suzanne
Abstract: A Statistical Comparator Interface provides a user with the capability to reduce vast amounts of raw data into a readily navigable and quickly comprehendible form. The Statistical Comparator Interface is embodied in two basic stages. In a data compilation stage, a compilation module, which is preferably implemented with computer software, receives the raw data and compiles the raw data into a format that is readily navigable by a navigation engine. This may include expanding the data through statistical computations and arranging the data in a data matrix complete with hierarchal indices. In a navigation stage, the navigation engine is employed to allow a user to generate data profiles from among the formatted data, including selecting a peer group with selected characteristics and selecting statistical comparisons to be calculated and displayed for the selected peer group. The navigation stage may also allow the user to select from among a plurality of graphical depiction schemes to display the selected statistical comparisons in a manner that is readily comprehendible to a lay, unindoctrinated user. The graphical display schemes preferably employ multivariate statistical methods such as MANOVA, discriminate analysis, multivariate multiple regression, etc., and multivariate graphing methods such as three-dimensional scatter plots and ordered profile surfaces to display the highly complex data in a readily understandable format.
2003 · Theoretical psychology: critical contributions
Brown, Bruce · Hendrix, Suzanne
Summary: In answer to Robinson's trenchant critique of the inadequacies of multivariate statistical decision theory in psychology and the reification of factor structure be replaced with a new way of dealing with data, through structuralndescription and graphics, "visual parables" if you will. In keeping with this structural emphasis, following a brief discussion of notable failings of the traditional approach, a number of examples of descriptive multivariate graphics are given with explanation. Three kinds of data are illustrated: an analysis of paradoxical results in vocal expression of emotion, an experimental study of supercomputer performance data (as a mechanistic analogue to human performance measurement), and a canonical correlation analysis of the correspondence of mutual fund performance to market indices for use in studies of contextually informed market trading behaviour. Future directions and practical applications are discussed.
2001 · Journal of Legal Education
1996 · Dissertation
Abstract: Many clinical trials are designed to compare treatment groups after a pre-determined length of time on treatment in order to allow the full treatment effect to be observed. If the scheduled duration of treatment is more than a few days, patients may withdraw from the study and appropriate handling of these patients may become critical to the proper interpretation of the efficacy results. We consider a protocol compliant (PC) or evaluable patients analysis, including only study completers, and an intent-to-treat endpoint analysis (ITT) using the last available value carried forward. We compare these two methods to an exposure adjusted (EA) method that includes all patients’ endpoint values in an analysis of covariance adjusting for varying exposure to study medication. These three methods are compared in terms of bias and efficiency under various dropout mechanisms including those unrelated to both the treatment group and the patient’s latent final response, as well as mechanisms related to these variables. We use a linear relationship between endpoint response and exposure to study medication. We show that under certain types of dropout, the ITT approach using the last available value carried forward is overly conservative and even biased at times. The PC analysis and the EA analysis preserve the type I error in most cases, and increase the power of the analysis over the ITT approach. We discuss the patterns of dropout that present the most difficulty, and indicate the best analysis for these situations.
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