| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
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| 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 |
| To evaluate the effect of single and multiple dosing of AZD1446 and a single dose of donepezil on Quantified electroencephalography (qEEG) and Event-related potentials (ERP) in patients with mild-to-moderate AD. |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the relationship between AZD1446/donepezil plasma concentrations and qEEG/ERP following single and multiple oral doses of AZD1446 and a single dose of donepezil, as applicable
2. To evaluate the correlation between changes in qEEG/ERP and changes in cognition, if applicable
3. To evaluate the time course of the effect on qEEG and ERP following different dosing regimens of AZD1446
4. To assess the safety and tolerability of single and multiple oral doses of AZD1446 in patients with AD.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of written informed consent from patient and caregiver before initiation of any study related procedures. Patients who are deemed incapable of providing informed consent may be enrolled if written informed consent has been obtained from the patient’s Legally Authorized Representative in accordance with local regulation
2. The patient and caregiver should understand, speak and read local language
3. The patient and the caregiver should be able to understand and comply with the requirements of the study, as judged by the investigator
4. Males and non-fertile females, 55-85 years, inclusive at day of enrollment
5. Clinical diagnosis of probable AD according to the NINCDS-ADRDA criteria
6. History of progressive worsening of memory and other cognitive functions for at least 12 months
7. A Hachinski Ischaemic Score ≤4, during enrollment (Visit 1).
8. CT or MRI scan within the past 6 months (performed after onset of dementia) consistent with the diagnosis of AD. If the CT/MRI test is older than 6 months, the patient will need to renew the CT/MRI to confirm the diagnosis
9. MMSE score 18-24
10. A body mass index (BMI=weight/height2) of 18-30 kg/m2 as calculated by the investigator at enrollment
11. Clcrea ≥60 mL/min estimated according to the formula by Cockcroft and Gault with S-Cr determined by Jaffe’s method (or if the enzymatic method is used, the S-Cr value used for calculating CLcrea should reflect the expected value as if the Jaffé method was used).
12. Male patients should be willing to use barrier contraception, ie, condoms, even if their partners are post-menopausal, surgically sterile or are using accepted contraceptive methods, from the first day of dosing until 3 months after the last dose of investigational product (IP)
13. Recordable P300
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| E.4 | Principal exclusion criteria |
1. Significant neurological disease or dementia other than AD, eg, mixed dementia, frontotemporal dementia and Parkinson’s disease, that may affect cognition or ability to complete the study
2. Possible, probable or definite vascular dementia in accordance with NINDS-AIREN criteria
3. Current major depressive disorder or other major psychiatric disorders according to the DSM-IV criteria
4. Current significant or unstable disease/disorder that, in the judgment of the investigator, is likely to deteriorate or affect the patient’s safety, influence cognitive assessments or affect ability to complete the study.
5. History of any malignant disease within the past 5 years with the exception of minor superficial skin diseases (ie, basal cell carcinoma and squamous cell carcinoma)
6. Poorly controlled diabetes mellitus, as judged by the investigator, or diabetes mellitus patient requiring any dose of insulin within the last 6 months. Insulin treated patients should be excluded since fluctuation in blood sugar may affect the cognitive assessments
7. Having known or suspected systemic serious infection (eg, HBV, HCV, HIV, tuberculosis) as judged by the investigator
8. Poorly controlled hypertension as judged by investigator
9. Myocardial infarction or acute coronary syndrome within the last year
10. Clinically significant ECG abnormalities as judged by the investigator based on assessment by a centrally located experienced cardiologist interpreting the ECG
11. Prolonged QTcF>450 msec or shortened QTcF<350 msec or family history of long QT syndrome
12. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results as judged by the investigator
13. Having a suspected or not sufficiently substituted hypothyreosis, vitamin B12 or folic acid deficiency
14. Clinically significant abnormal findings in physical examination or vital signs that may affect the ability of the patient to complete study procedures, patient safety or data interpretation, as judged by the investigator
15. Having one or more of the following histamine associated criteria
- History of severe allergy/hypersensitivity reactions including severe food allergy as judged by the investigator
- History of Quincke oedema, angiooedema or urticaria pigmentosa, or history of repeated episodes of urticaria, regardless causative agent
- History or present symptoms or signs of asthma of any severity as judged by the investigator
- History of hypersensitivity to drugs of a similar class to AZD1446 as judged by the Investigator
- Eosinophilia (ie, > upper limit of normal local lab reference limit, at enrollment)
16. Impaired vision and hearing making cognitive testing difficult as judged by the investigator
17. Women who are of childbearing potential, ie, not surgically sterile or post-menopausal for at least 12 months
18. Male patients planning to father a child or donate sperm during the study period and within 3 months after last intake of study drug
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| E.5 End points |
| E.5.1 | Primary end point(s) |
qEEG and event-related potentials (ERPs) will be measured to allow comparison of single and multiple oral administration of AZD1446 with single administration of donepezil compared to placebo:
- qEEG parameters derived from measurements on the 28 electrodes
- Event-related potentials (ERPs) measured by means of Auditory P300 and MMN variables from all 28 leads
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| 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 | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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