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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.
10 publications
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2010 · European Neuropsychopharmacology
2010 · Alzheimer's & Dementia
Background: In patients with Alzheimer's disease (AD), it is of interest to determine whether therapy can prevent worsening across multiple clinical domains. 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 worsening on three possible outcomes: a clinician's assessment of global status (CGI-C), a measure of the patient's language and functional communication (the Functional Linguistic Communication Inventory [FLCI]), and a caregiver's assessment of the patient's functional communication skills (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 who experienced any decline from baseline on the three outcome measures (CGI-C >4, FLCI <0, or ASHA-FACS <0). We also examined the subsets of patients in the CGI-C >4 subset who evidenced greater-than-mild decline on the FLCI (FLCI <-3) and ASHA-FACS (ASHA-FACS <-10). We then used Generalized Estimating Equations to compare treatment groups in terms of proportions of patients who fulfilled these criteria for double and triple outcome measure combinations at endpoint and overall (i.e., throughout the trial). Results: In the three possible double-outcome measure combinations for patients experiencing any decline, memantine treatment (vs. placebo) significantly prevented worsening at endpoint and overall for the ASHA-FACS/CGI-C combination and overall for the ASHA-FACS/FLCI combination (P < 0.05). No significant differences in prevention of worsening were observed for the FLCI/CGI-C double-outcome combination or for the triple-outcome combination. In the group that experienced greater-than mild decline, all three double-outcome combinations and the triple-outcome combination demonstrated significant prevention of worsening in the memantine group at endpoint and overall (P < 0.05). Conclusions: In patients with moderate AD, memantine is associated with a prevention of worsening in functional communication and global clinical status.
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
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