Angelika Caputo

Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial.

OBJECTIVE To evaluate the efficacy, safety, and tolerability of fixed-dose agomelatine 25 and 50 mg/d in the treatment of outpatients with moderate-to-severe major depressive disorder (MDD) compared to placebo. METHOD In this 8-week, multicenter, double-blind, parallel-group trial, patients with DSM-IV-defined MDD were randomly assigned (1:1:1) to receive a once-daily dose of agomelatine 25 mg, agomelatine 50 mg, or placebo. The primary efficacy measure was the change from baseline to week 8 in the clinician-rated 17-item Hamilton Depression Rating Scale (HDRS(17)); other efficacy measures were the clinical remission and response rates (measured by HDRS(17)), Clinical Global Impressions scales, Hospital Anxiety and Depression Scale (HADS) score, subjective measures on sleep, and the overall quality of life. The study was conducted between December 2006 and January 2008. RESULTS Agomelatine 25 mg/d was more efficacious based on the HDRS(17) total score (P = .01) compared to placebo throughout the treatment period, whereas for agomelatine 50 mg/d, statistically significant reduction in HDRS(17) total score could be observed from weeks 2 to 6 but not at week 8 (P = .144). A higher proportion of patients receiving agomelatine 25 mg/d showed clinical response (P = .013), clinical remission (P = .07), and improvement according to the Clinical Global Impressions-Improvement scale (P = .065) compared to those receiving placebo. No statistically significant difference between patients receiving agomelatine 50 mg/d compared to placebo on clinical response (P = .116) or clinical remission (P =. 457) was observed. HADS score, quality of sleep, and quality of life significantly improved with agomelatine 25 mg/d compared to placebo. Both agomelatine doses were safe and well tolerated, although clinically notable aminotransferase elevations were observed transiently in the agomelatine 50 mg/d group. CONCLUSIONS Agomelatine 25 mg/d was effective in the treatment of patients with moderate-to-severe MDD and was safe and well tolerated. Agomelatine 50 mg/d provided evidence for its antidepressant efficacy until week 6 and was also safe and well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00411242.

Randomized, Double-Blind, Parallel-Group, 48-Week Study for Efficacy and Safety of a Higher-Dose Rivastigmine Patch (15 vs. 10 cm2) in Alzheimer’s Disease

Aim: Determine whether patients with Alzheimer’s disease demonstrating functional and cognitive decline, following 24–48 weeks of open-label treatment with 9.5 mg/24 h (10 cm2) rivastigmine patch, benefit from a dose increase in a double-blind (DB) comparative trial of two patch doses. Methods: Patients meeting prespecified decline criteria were randomized to receive 9.5 or 13.3 mg/24 h (15 cm2) patch during a 48-week, DB phase. Coprimary outcomes were change from baseline to week 48 on the Instrumental Activities of Daily Living domain of the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-IADL) scale and the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog). Safety and tolerability were assessed. Results: Of 1,584 patients enrolled, 567 met decline criteria and were randomized. At all timepoints, ADCS-IADL and ADAS-cog scores favoured the 13.3 mg/24 h patch. The 13.3 mg/24 h patch was statistically superior to the 9.5 mg/24 h patch on the ADCS-IADL scale from week 16 (p = 0.025) onwards including week 48 (p = 0.002), and ADAS-cog at week 24 (p = 0.027), but not at week 48 (p = 0.227). No unexpected safety concerns were observed. Conclusions: The 13.3 mg/24 h rivastigmine patch significantly reduced deterioration in IADL, compared with the 9.5 mg/24 h patch, and was well tolerated.

Planung einer klinischen Studie: Wie viele Patienten sind notwendig?

Die Grose einer klinischen Studie, d.h. die Anzahl der Patienten, die aufgenommen werden sollen — auch Fallzahl oder Stichprobenumfang genannt — ist ganz entscheidend fur die Aussagekraft einer Studie. Sie sollte vor Beginn der Studie festgelegt und mit Begrundung im Studienprotokoll festgehalten werden. In diesem Kapitel wird zunachst anhand eines fiktiven Beispiels die Zielsetzung der Fallzahlplanung erlautert. Grundlegende statistische Schlussweisen bieten den geeigneten Rahmen, um diese Ziele formal darzustellen und letztlich zu konkreten Formeln fur die Bestimmung des geeigneten Stichprobenumfangs fur eine klinische Studie zu gelangen. Die Fallzahlplanung wird im Folgenden an Beispielen von Studien mit unterschiedlichen Zielkriterien erlautert, die zum Teil bereits in anderen Kapiteln dargestellt wurden.

High-dose 13.3 mg/24 h rivastigmine transdermal patch demonstrates efficacy on instrumental activities of daily living: Individual item analysis

Background: OPTIMA, a 48-week randomized, double-blind (DB) study, compared the efficacy and safety of 13.3 and 9.5 mg/24 h rivastigmine patches in patients with AD meeting functional and cognitive decline criteria during an initial open-label (IOL) phasewith 9.5 mg/24 h patch. The current analysis investigated the efficacy of 13.3 mg/24 h patch on the autonomy in instrumental activities of daily living (IADL) in patients by disease severity and time-to-meet decline criteria.Methods: Patients receiving rivastigmine patch 9.5 mg/24 h, were assessed at Weeks 24, 36 and 48 of the IOL phase for functional (investigators’ judgement) and cognitive decline ( 2-point decrease in Mini-Mental State Examination [MMSE] score from previous visit OR 3-point decrease from baseline). Decliners entered the randomized DB phase (9.5 or 13.3 mg/24 h). Co-primary outcomes included change from DB-baseline at Week 48 on the AD Cooperative Study (ADCS)-IADL scale. Prospective subgroup analyses were efficacy on ADCS-IADL by: disease severity at DB-baseline (moderate [MMSE 10 18] versus moderate-to-severe [MMSE 3 18]); and time-to-meet decline criteria ( 36 versus >36 weeks). Results: The mean DB-baseline ADCS-IADL score was higher with 13.3 mg/24 h, compared with 9.5 mg/ 24 h patch, for patients with moderate (26.7 and 24.5, respectively) or moderate-to-severe disease (25.3 and 22.8, respectively). At all time points, regardless of disease severity, slower decline in ADCS-IADL score was observed with 13.3 versus 9.5 mg/24 h patch. The mean DB-baseline ADCS-IADL score was higher with 13.3 mg/24 h, compared with 9.5 mg/ 24 h patch, for patients meeting decline criteria 36 weeks (27.1 and 24.5, respectively), but comparable for patients meeting decline criteria >36 weeks. Regardless of time-to-meet decline criteria, decline in ADCS-IADL score was less with 13.3 mg/24 h patch during Weeks 16 to 48.The superiority of the 13.3 mg/24 h patch compared with the 9.5 mg/ 24 h patch was confirmed by statistical comparisons adjusted for the corresponding baseline value for the different subgroup analyses. Conclusions: High-dose (13.3 mg/24 h) rivastigmine patch demonstrates superior efficacy on functional outcomes and provides additional benefits to patients with AD, compared with 9.5 mg/24 h patch, regardless of their disease severity or time-to-meet decline criteria.

A Testing Strategy With Adaptive Dose Selection and Two Endpoints

ABSTRACT The article deals with the design of a complex clinical trial with multiple doses of an experimental treatment tested against a control treatment, interim analyses and several endpoints characterizing treatment success. The closed test principle, methods from group sequential testing, and combination test methodology are combined to control the familywise error rate (FWER) when testing for treatment benefit. We also discuss strategies for utilizing the correlations between some of the relevant test statistics.

WHY AND HOW WE THINK THAT CLINICAL TRIALS OF THERAPIES FOR ALZHEIMER’S DISEASE CAN BE SUCCESSFUL: A SIMULATION PLATFORM FOR PRECLINICAL AD

population had DDIs (average of 7.12 per person, SD 6.7), and 37% had DGIs (average of 1.98 per person, SD 1.3). 9% of the population had an ACB score of three or higher. The algorithm then provided actionable advice for physicians to revise medication issues. Conclusions:MM is a complex task, amplified when dealing with an older population who are not only on more medications, but also have existing comorbidities and alternate pharmacokinetics. CDSS can better enable MM, through its ability to consider a full list of medications, comorbidities, and complex medical recommendations (such as Beers Criteria), reduce redundancies, reduce DDIs and DGIs, and recommend better alternatives. CDSS can generate effective and highly-usable guidelines for each recommended change (deprescribing methodologies, changing dosages or formulations, replacing with alternatives, and scheduling). Continued study of the impact of medications on this population with cognitive decline is warranted.

PSYCHOSOCIAL OUTCOMES OF APOE E4 GENOTYPE DISCLOSURE IN THE GENERATION STUDY

O4-08-03 PSYCHOSOCIAL OUTCOMES OF APOE E4 GENOTYPE DISCLOSURE IN THE GENERATION STUDY Angela R. Bradbury, Jason Karlawish, J Scott Roberts, Brian L. Egleston, Linda Patrick-Miller, Elisabeth McCarty Wood, Scott YH. Kim, Jan Jaeger, Neeraja Reddy, Cara Cacioppo, Dare Henry-Moss, Stephanie Jideama, Demetrios Ofidis, Fonda Liu, Angelika Caputo, Marie-Emmanuelle Riviere, Mauritz Bezuidenhoudt, Carolyn Langlois, Eric M. Reiman, Pierre N. Tariot, Jessica B. Langbaum, University of Pennsylvania, Philadelphia, PA, USA; University of Michigan, Ann Arbor, MI, USA; Fox Chase Cancer Center, Philadelphia, PA, USA; Independent Consultant, Chicago, IL, USA; National Institutes of Health, Bethesda, MD, USA; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Novartis Pharma AG, Basel, Switzerland; Novartis Pharma, Basel, Switzerland; Banner Alzheimer’s Institute, Phoenix, AZ, USA; Arizona Alzheimer’s Consortium, Phoenix, AZ, USA. Contact e-mail: angela.bradbury@uphs.upenn.edu

ESTIMAND IN EARLY ALZHEIMER’S DISEASE: PROGRESS UPDATE FROM THE INTERNATIONAL ALZHEIMER’S DISEASE SCIENTIFIC WORKING GROUP (AD SWG) SUBSTREAM

(CSF) and brain of rodents and primates, as well as in the CSF of patients with AD. In a previous Phase-3 trial (EPOCH) verubecestat was not effective for slowing clinical progression in participants with mild-to-moderate AD despite near maximal reduction of CSF Ab. Since Ab deposition takes place many years before clinical symptoms become apparent, implementing treatments targeting Ab earlier in the disease process may be effective. Here we report on the design of the APECS trial in prodromal AD.Methods: APECS (clinicaltrials.gov NCT01953601) is an ongoing Phase-3 randomized, double-blind, 24-month, placebo-controlled trial of verubecestat (12mg and 40mg) in participants with prodromal AD/amnestic mild cognitive impairment due to AD. Key entry criteria included: subjective memory decline with gradual onset and slow progression for at least 1 year, corroborated by an informant; objective impairment in episodic memory 1 SD below the appropriate population mean on the delayed memory index score of the Repeatable Battery for the Assessment of Neuropsychological Status; positive Ab imaging PET scan; Mini Mental State Examination score 24. Key exclusion criteria included diagnosis of dementia or other relevant neurological or psychiatric disorder. The primary efficacy endpoint is change-from-baseline in the Clinical Dementia Rating – Sum of Boxes score at Month 24. Secondary endpoints include changes in cognitive test scores, changes in biomarkers, and time to progression to AD. Results: 4483 people were screened and 1454 were randomized between 2013 and 2017 (screening failure rate of 68%). Preliminary baseline data showed a trial population with the following demographic characteristics: 53%male, mean (SD) age of 71.4 (7.2) years, 81%white (17%Asian, 1%other), 51%with an undergraduate degree or higher, 46%usingAD treatment, 69%APOE4 carriers, andmean (SD)Mini Mental State Examination score of 26.3 (1.8). The trial is expected to complete in 2019. Conclusions: Results from the APECS trial will help inform whether blocking Ab production is effective in slowing clinical progression in participants with prodromal AD.

Safety and tolerability of active immunotherapy cad106 in two phase ii studies in Alzheimer's patients

Background: a-Synuclein (aS) assembly has been implicated as a critical step in the development of Lewy body diseases such as Parkinson’s disease. Melatonin (Mel), a secretory product of the pineal gland, is known to have beneficial effects such as an antioxidant function and neuroprotection. Recently, Mel has been shown by immunostaining to inhibit aS assembly. Methods: To elucidate whether Mel has an anti-assembly effect, here we used circular dichroism spectroscopy (CD), photo-induced cross-linking of unmodified proteins (PICUP), thioflavin S fluorescence (ThS), size exclusion chromatography (SEC), electron microscopy (EM) and atomic force microscopy (AFM) to examine the effects of Mel on the assembly of aS. We also examined the effects ofMel on aS-induced cytotoxicity by assaying 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) metabolism in aS-treated, primary neuronal cells. Results: Initial studies revealed that Mel blocked aS fibril formation as well as destabilizing preformed aS fibrils. Subsequent evaluation of the assembly-stage specificity of the effect showed that Mel was able to inhibit protofibril formation, pre-protofibrillar oligomerization, and initial coil-a-helix/s-sheet secondary structure transitions. Importantly, Mel had protective effects in assays of cytotoxicity in which Mel was mixed with aS prior to peptide assembly. Conclusions: These data suggest a mechanism of action for Mel, inhibition of assembly of toxic polymers and protection of neurons from their effect.

Testen von Hypothesen

Eine Verbraucherzentrale mochte uberprufen, ob ein bestimmtes Milchprodukt Ubelkeit bei den Konsumenten auslost. In einer Studie mit zehn Personen wird bei sieben Personen nach dem Genus dieses Milchprodukts eine auftretende Ubelkeit registriert. Uberprufen Sie zum Signifikanzniveau α = 0.05 die statistische Nullhypothese, das der Anteil der Personen mit Ubelkeitssymptomen nach dem Genus dieses Produkts in der Grundgesamtheit hochstens 60 % betragt. Geben Sie zunachst das zugehorige statistische Testproblem an.