E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with mild to moderate Alzheimer's Desease |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
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 |
The primary objective of this study is to evaluate the safety and tolerability of 3 dose regimens of AZD1446 compared to placebo as an add-on treatment to donepezil for 4 weeks in patients with mild to moderate Alzheimer’s disease (AD) |
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E.2.2 | Secondary objectives of the trial |
· To evaluate any effect of AZD1446 as an add-on treatment to donepezil on the pharmacokinetics (PK) of donepezil · To characterize the PK of AZD1446 as an add-on treatment to donepezil in AD patients, using population analysis · To evaluate the effects of 2 different doses of AZD1446 as an add-on treatment to donepezil compared to placebo on changes from baseline in global functioning using Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC, Shneider et al, 1997) · To analyse Apolipoprotein E genotype in relation to drug response and other clinical endpoints
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of written informed consent 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 patient’s Legally Authorised Representative in accordance with the local regulation. Provision of written informed consent from the caregiver 2. Female and male patients aged 60 to 85 years, inclusive at the day of enrolment (Visit 1) 3. Male patients should be willing to use barrier contraception, ie condoms, even if their partners are post-menopausal, be surgically sterile or are using accepted contraceptive methods, from the first day of dosing until 3 months after the last dose of the investigational product 4. Clinical diagnosis of probable Alzheimer’s disease according to the NINCDS-ADRDA criteria 5. History of progressive worsening of memory and other cognitive functions for at least 12 months prior to Visit 1 6. Hachinski ischaemic score ≤ 4 7. CT/MRI results consistent with the diagnosis of AD and not older than 12 months prior to Visit 1. The CT/MRI should have been performed in order to support the diagnosis of AD, or after the patient has been diagnosed with AD 8. Treatment with stable dose of donepezil (10 mg) for at least 3 months (12 weeks) prior to inclusion in the study (Visit 1). The patient must continue to take the same dose of donepezil during the whole study (V1 till follow-up) 9. MMSE score 12-24 10. Body mass index (BMI=weight/height2) of 18-30 kg/m2 as calculated by the investigator at enrolment 11. Clcrea ≥ 60 ml/min estimated according to the formula by Cockroft 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 Jaffe method was used) 12. The patient should be willing to donate a blood sample for determination of APOE genotype 13. The patient should have an appropriate caregiver at home, or in a community dwelling (caregiver who sees the patient at least 2-3 times a week and is capable of giving appropriate information regarding patient’s health, functioning and behaviour). The same caregiver is required for all visits 14. The patient and the caregiver should be able to understand, speak and read local language. In case of language dysfunction due to Alzheimer’s Disease, the patient should at least formerly have been able to understand, speak and read local language. The caregiver should be able to understand, speak and read local language. 15. The patient and the caregiver should be able to understand and comply with the requirements of the study, as judged by the investigator 16. For inclusion in the optional exploratory genetic research, patients must provide informed consent for optional exploratory genetic research. If a patient declines to participate in the optional exploratory genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this CSP, as long as they consent. |
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E.4 | Principal exclusion criteria |
1. Significant neurological disease or dementia other than Alzheimer’s Disease, eg, mixed dementia, frontotemporal dementia, Lewy body 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 episode or symptoms of major depressive disorder or other major psychiatric disorders according to the DSM-IV Axis I criteria 4. Current significant or unstable disease eg, epilepsy 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. Myocardial infarction or acute coronary syndrome within the last year 7. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following or clinically significant as judged by investigator: − Systolic BP >160 mm Hg − Diastolic BP >90 mm Hg − Heart rate <40 or >85 beats per minute − Significant orthostatic reaction as judged by the investigator 8. Poorly controlled diabetes mellitus, as judged by the investigator, or diabetes mellitus patient requiring any dose of insulin during the last 6 months 9. Known or suspected systemic infection (eg, HBV, HCV, HIV, tuberculosis) as judged by the investigator 10. 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 11. History of allergy/hypersensitivity reactions: − History or present symptoms or signs of severe allergy/hypersensitivity reactions including severe food allergy, as judged by the investigator − History or present symptoms or signs 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 12. Clinically significant ECG abnormalities as judged by the investigator based on assessment by a centrally located experienced cardiologist interpreting the ECG 13. Prolonged QTcF >450 msec or shortened QTcF <350 msec or family history of long QT syndrome 14. Impaired vision and hearing making cognitive testing difficult as judged by the investigator 15. Any clinically significant abnormalities in clinical chemistry, haematology, B12 or urinalysis results as judged by the investigator 16. Use of smoking cessation therapy within 4 weeks prior to enrolment visit and during the study. Smoking cessation therapy including but not limited to buproprion, varenicline; any dosage form of nicotine replacement therapy 17. Use of memantine or any AchEIs (Acetylcholine-esterase inhibitors) other than donepezil within 3 months prior to the first administration of study drug and during the study 18. Use of certain drugs with narrow therapeutic range (such as, but mot limited to: aminoglycoside antibiotics, lithium, digoxin, methotrexate, metformin) within 4 weeks prior to the first administration of study drug 19. Use of other anti AD drugs, psychostimulants, mood stabilizers, antipsychotics, anticonvulsants, anticholinergics, urinary spasmolytics, anti-parkinson drugs, antihistamines, anti-asthmatics or beta blockers within 4 weeks prior to enrolment 20. Use of anxiolytics, antidepressants and hypnotics 4 weeks prior to enrolment (Visit 1), unless on regular dosing for more than 4 weeks 21. Use of any strong inhibitors of CYP3A4 enzymes during the last 4 weeks prior to the first administration of study drug and during the study 22. Current clinically significant or unstable respiratory, gastrointestinal, heart, cerebrovascular, haematological, hepatic, renal disease or other major disease as judged by the investigator 23. Known or suspected drug or alcohol abuse or addiction as defined by the DSM-IV and not in full remission 24. Positive toxicology test for illegal or non-prescribed substances of abuse at screening 25. Male patients planning to father a child or donate sperm during and for 3 months after the last intake of study drug
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome variables (safety): • Adverse events (AEs) • Laboratory variables (blood, urine) • Vital signs • Physical examination • Electrocardiogram (ECG) • Columbia Suicide Rating Scale (C-SSRS, Posner et al 2007) |
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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 | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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
| 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |