Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease

This randomized clinical trial evaluates whether treatment with the dopaminergic agonist rotigotine has an effect on cognitive function in patients with mild to moderate Alzheimer disease in Italy.


STUDY PROTOCOL
the absence of overt extra-pyramidal symptoms (Pizzolato et al., 1996). Kemppainen  Alzheimer's disease patients as compared to controls. This reduction was found to be associated 216 with both cognitive (Kemppainen et al., 2003) and behavioral abnormalities in Alzheimer's disease 217 patients (Tanaka et al., 2003). Localization studies of dopamine receptors in Alzheimer's disease 218 brains have shown a preferential reduction of D2-like receptors in the hippocampus and prefrontal 219 cortex (Kemppainen et al., 2003;Kumar and Patel, 2007). Prolonged exposure to Aβ would (TMS) during electroencephalography (EEG) will allow us to understand how dopamine agonists 242 are able to modulate the cortical activity of the prefrontal cortex in AD patients (Kähkönen et    The primary objective of this study is to test the hypothesis that therapy with Rotigotine could have 258 a relevant clinical impact on cognitive impairment in Alzheimer's disease patients as compared 259 with placebo. The primary objective will be evaluated using a study endpoint at 24 weeks after 260 initiation of treatment. The primary objective will be assessed using a Generalized Linear Mixed  Scale-Cognitive (ADAS-Cog), in which the specific hypothesis is that the cognitive decline at the 263 end of the treatment phase for RTG will be significantly less than that for placebo.

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The secondary objectives of this study are as follows: 266  To test the hypothesis that RTG will slow the rate of decline associated with AD in the 267 activities of daily living, as assessed with the Alzheimer's disease Cooperative Study -268 Activities of Daily Living (ADCS-ADL), using a GLMM for repeated measures.    At or before Visit 1, the study will be explained to the patient and caregiver. In the screening phase, 306 all patients will undergo an extensive clinical investigation, including interviews on their medical 307 history, a full neurological examination, the MMSE, a complete blood screening, 308 neuropsychological assessment, neuropsychiatric evaluation, and magnetic resonance imaging. In   After recruitment and baseline assessments, AD patients will be assigned to RTG or PLC as add on 341 to current AChEI therapy (donepezil or rivastigmine). We will use the Neupro® (Rotigotine

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Transdermal System), a transdermal delivery system that provides rotigotine, a non-ergolinic DA 343 13 agonist, currently used for treatment of Parkinson's disease. When applied to intact skin, Neupro is 344 designed to continuously deliver rotigotine over a 24-hour period. The precise mechanism of action 345 of rotigotine, as a treatment for Parkinson's disease, is unknown although it is suggested to be 346 related to its ability to stimulate D2 receptors within the brain. All of the non-ergoline agonists  All treatments will be administered for 24 weeks with no interruptions. All treatments will be 357 administered for 24 weeks with no interruptions. Rotigotine will be administered through a 4 mg 358 transdermal patch (Neupro, UCB pharma), after having started with a 2 mg patch for 1 week.

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Transdermal patches of rotigotine have a release surface area of 10 or 20 cm 2 and contain 4.5 or 9 360 mg of rotigotine to release respectively 2 or 4 mg during a 24-hour period when applied to intact 361 skin. The placebo transdermal patch contained in cardboard packaging will be identical to the 362 rotigotine except for the absence of rotigotine. Eligible patients will be males and females with mild to moderate AD, as specified in the entry 368 criteria that follow. Entered patients who meet all of the inclusion criteria and are not excluded by 369 any of the exclusion criteria will be randomized and proceed to Evaluation Phase.       Neuropsychiatric Inventory (NPI). The NPI assesses behavioral disturbances in dementia. The NPI 508 is reliable and valid (Cummings, 1994) and has been reported to be sensitive to the effects of tacrine 509 (Kaufer et al., 1996). The NPI measures the following behavioral areas: delusions, hallucinations,

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A clinical study AE is any untoward medical event associated with the use of a drug or drug 535 delivery system in humans. AE collection begins after the patient has signed informed consent and 536 has received study drug. If a patient experiences a AE after signing informed consent, but before 537 receiving study drug, the event will not be collected unless the investigator feels the event may have 538 been caused by a protocol procedure.

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At each clinic visit, AEs will be recorded, vital signs will be measured and physical and 540 neurological examination will be performed. An independent Data Monitoring Committee will 541 monitor the patients' safety according to the Data Monitoring Committee Charter. The principal investigator is responsible for ensuring that the patient understands the potential risks 547 and benefits of participating in the study, including answering any questions the patient may have 548 throughout the study and sharing in a timely manner any new information that may be relevant to 549 the patient's willingness to continue his or her participation in the trial.

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The Informed Consent Form (ICF) will be used to explain the potential risks and benefits of study 551 participation to the patient/caregivers in simple terms before the patient is entered into the study,

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This study will be conducted in accordance with: 3) Applicable laws and regulations.

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The investigator or designee will promptly submit the protocol to applicable ERB. An identification 566 code assigned by the investigator to each patient will be used in lieu of the patient's name to protect 567 the patient's identity when reporting AEs and/or other trial-related data. Alzheimer's disease patients (Koch et al., 2014). In that pilot study, a significant (although unpowered) 583 difference was observed in pre-post (12 weeks) treatment with rotigotine in n=7 patients in both the 584 cognitive measures MMSE (mean pre=21.73, SD=4.14; mean post=23.23, SD=3.93) and in FAB (mean 585 pre=10.85, SD=4.43; mean post=12.32, SD=4.48). Treatment duration of the present study is twice larger 586 than the one of the pilot study thus a larger effect size is expected. However, for precautionary reasons, we 587 consider the same effect sizes found in the previous work (equal to 0.48 for MMSE and equal to 0.42 for 588 FAB computed as post-pre means over standard deviation of differnce post-pre), for the sample size 589 calculation of the present study. In detail, adopting a two-tailed paired t-test, with type I error alpha=0.05 and 590 a plausible correlation between pre-post measured variables of 0.7, the FAB effect size equal to 0.42 requires 591 a minimum sample of n=46 for reaching a power of 0.8. For MMSE, this sample size allows to reach a 592 power of 0.9. The minimum total sample size was then augmented up to N=92 considering the matched 593 placebo group. 594

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Subjects who meet all criteria for enrollment will be randomized to double-blind treatment.

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Randomization will be performed and assigned independently by a statistician working in an 597 independent institution, held centrally, and not divulged to any other person involved in the trial 598 until after database lock. In order to obtain homogeneous and balance study groups in terms of age, 599 sex and APOE carriers, an adaptive randomization will be adopted; more specifically, a covariate-600 adaptive randomization will be performed, i.e. a randomization procedure that uses past group 601 assignments and subject covariate values to select the probability of future group assignments, with the 602 objective to balance group assignments within covariate profiles (Lin et al. 2016 Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 611 0.05; 2-sided confidence intervals will be displayed with a 95% confidence level. All tests of 612 interactions between treatment and other factors will be conducted at an alpha level of 0.05. All 613 analyses will follow the intent-to-treat (ITT) principle unless otherwise specified. An ITT analysis 614 is an analysis of data by the groups to which subjects are assigned by random allocation, even if the 615 subject does not take the assigned treatment, does not receive the correct treatment, or otherwise 616 does not follow the protocol.

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Baseline characteristics as well as the co-primary and secondary efficacy measures will be 619 summarized for the ITT and per-protocol populations by treatment group and overall. Tabulations 620 of the number and percentage of subjects included in each analysis set, by treatment group and 621 overall, will be provided. Reasons for exclusion from analysis datasets will also be provided. The patient's age, gender, height, body weight, tobacco use, alcohol use, caffeine use, years of 624 education, work status, time since onset of first AD symptoms, time since diagnosis, MMSE at Visit 625 1, APOE4 carrier status (carrier [ε2/ε4, ε3/ε4, ε4/ε4], noncarrier [ε3/ε3, ε2/ε2]), APOE4 genotype 626 (ε2/ε4, ε3/ε4, ε4/ε4, no ε4) and AChEI use at baseline will be recorded. Baseline characteristics will 627 25 be summarized for the ITT and per-protocol populations by treatment group and overall. Summaries 628 will include descriptive statistics for continuous and categorical measures. Pearson's chi-square test 629 will be used for treatment group comparisons of categorical data. For continuous data, t-test or 630 corresponding non-parametric test (Mann-Whithney) will be used for the group comparing. Normality assumption of end-points variables will be assessed by inspection of the distribution 633 plots and by Kolmogorov-Smirnov and Shapiro-Wilk tests. Preliminary descriptive analyses will be 634 performed by means, frequencies, standard deviations (SD) and percentages. Comparison of socio-635 demographic and clinical features between the study groups at baseline will be performed through t-636 test or Mann-Whitney tests.

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The longitudinal assessment of the end-points across groups will be performed through Generalized  factors. In detail, GLMMs for Gaussian data with identity link function will be applied for ADAS-643 Cog, ADCS-ADL and FAB, whereas GLMM for Poisson data, with log-link function, will be used 644 for NPI. The GLMMs on MMSE, ADAS-Cog and FAB will be adjusted for age and education. To 645 evaluate the treatment effects on TMS/EEG data, we will use repeated-measures ANOVAs with 646 between-subjects factor group and within-subject factors time.

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To evaluate the treatment effects on cortical activity, a repeated-measures ANOVA with between-648 subjects factor "group" and within-subject factors "time" will be planned. Repeated-measures 649 mixed ANOVA with between-subjects factor "group" and within-subject factors "time" will be 650 planned to evaluate the treatment effects on oscillatory activity. Prior to undergoing ANOVA 651 procedures, normal distribution of clinical, behavioral and neurophysiological data will be assessed