E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amnestic Mild Cognitive Impairment (aMCI) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009846 |
E.1.2 | Term | Cognitive impairment |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of the study is to define the short-term effects of the existing Alzheimer's Disease (AD) symptomatic treatment compound donepezil on cognitive EEG/ERP endpoints and olfactory discrimination in normal elderly and amnestic mild cognitive impairment (aMCI) cohorts. The overall goal of the study is to develop EEG/ERP measures that can detect pharmacodynamic effects in subjects with aMCI and elderly controls, after short-term treatment with medications that have been approved for symptomatic treatment in AD. These measures can then be used for the future assessment of potential novel treatments for AD. |
|
E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria:
Older Controls • aged between 65-80 years • absence of symptoms of cognitive impairment • MMSE score of 27 or higher • test scores on the neuropsychological battery (see below) that are not more than 1 SD below age-adjusted norms
aMCI Subjects • aged between 65-80 years, • symptoms of cognitive impairment for at least 6 months, • the diagnosis of ‘not demented’ (i.e. CDR status of 0 or 0.5). • must score greater than 1.5 SD below aged norms on at least one of the following: WMS-III logical memory, visual reproduction or face recognition • only include as aMCI delayed measures and not immediate measures. • meet consensus criteria for amnestic MCI (a-MCI; Winblad et al, 2004)
|
|
E.4 | Principal exclusion criteria |
Exclusion Criteria
• Active medical disease or psychiatric illness • History of head injury, stroke, epilepsy/seizure disorder, heart attack, syncopal or pre-syncopal episode, episodes of unexplained loss of consciousness • Clinically significant abnormalities on screening ECG, including but not limited to conduction abnormalities or heart rate <55 beats / min as judged by the investigator • Clinically significant abnormalities on screening laboratory tests as judged by the investigator • History of major psychiatric illness • Currently taking psychotropic medication, antidepressants, benzodiazepines or oral steroids. • History or presence of alcohol/drug abuse/dependency • Scoring above cut-offs on screening anxiety and depression scales (the Hospital Anxiety and Depression Scale (HADS) depression score >8, anxiety score >8 . • If English is not their first language • Any contraindications to taking donepezil as specified in the Summary of Product Characteristics, including history or presence of asthma, chronic obstructive airways disease, peptic ulcers and seizures. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The following endpoints are examples of a few of a large number of potential endpoints from a large quantity of EEG data:
1. Resting EEG Extraction of background spectral power (delta, theta, alpha, beta) Reduced alpha blocking/desynchonisation (eyes open vs eyes closed) Eyes open/eyes closed – damping ratio (magnitude of change in synchronization)
2. SARTfixed Increased amplitude in P1 and NI components on trial 2 N300 seen as phasic negativity over the occipitoparietal scalp between 300 &500ms on trial 2. A later prospective positivity broadly distributed (500-1000ms) over parietal areas. Late Positive 1 (LP1) will be observed 550-800ms following trial 2 onset and will exhibit divergence between correct and incorrect target (3) responding.
3. Learn/No Learn Task (ERP components of relevance) Cue information: Increased sensory facilitation of cue information (early ERP components P1, N1) Increased anticipatory potentials linked to biasing brain attentional set (parietal, midline frontal and lateral frontal).
Word encoding: Increased sensory processing of learn word information relative to no-learn word & letter strings. Components linked to word/non-word processing (latency & amplitude) Increased N2/P3 amplitude
Word recognition: Recognition memory studies have suggested that event-related brain potentials (ERPs) may tap into several different memory processes. In particular, two ERP components have been hypothesized as related to familiarity (FN400 old/new effect, 300–500 ms, anterior) and recollection processes (parietal old/new effect, 400–800 ms, posterior).
Word recall: Spectral power changes during recall (e.g., theta activity – synchronization of theta during recall). Differences between silent recall, recall old words, recall names family/friends
EEG/ERP interactions: Novel interactions between spectral markers and ERP components
4. Auditory Oddball Standard/target design (P3b) Standard/target/distractor (P3a) Reductions in the P3a ERP amplitude and latency (associated with phasic attention to novel events and linked to ACC and hippocampal function) – ie., responding to the unexpected) Reductions in the P3b ERP amplitude and latency (associated with memory storage operations and interactions between hippocampal and parietal cortices) – ie., updating memory and acting ***Olfactory endpoints |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last visit of the last subject undergoing the trial. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |