Safety, Tolerability and Pharmacokinetics of 3 Dose regimens of AZD1446 vs. Placebo as an Add-on Treatment to Donepezil: A Multi-centre, Double-blind, Randomised, Placebo controlled, Parallel group Phase IIa Study in Patients with Mild to Moderate Alzheimer’s Disease during 4 weeks of Treatment

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2009-015525-37-CZ
• Date of registration: 27/10/2009
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: Safety, Tolerability and Pharmacokinetics of 3 Dose regimens of AZD1446 vs. Placebo as an Add-on Treatment to Donepezil: A Multi-centre, Double-blind, Randomised, Placebo controlled, Parallel group Phase IIa Study in Patients with Mild to Moderate Alzheimer’s Disease during 4 weeks of Treatment
• Scientific title: Safety, Tolerability and Pharmacokinetics of 3 Dose regimens of AZD1446 vs. Placebo as an Add-on Treatment to Donepezil: A Multi-centre, Double-blind, Randomised, Placebo controlled, Parallel group Phase IIa Study in Patients with Mild to Moderate Alzheimer’s Disease during 4 weeks of Treatment
• Date of first enrolment: 13/01/2010
• Target sample size: 60
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-015525-37
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Czech Republic, Hungary

Key inclusion & exclusion criteria

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 =50 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) (see section 11.4)
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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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, anticholin

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with mild to moderate Alzheimer's Desease
MedDRA version: 12.0 Level: LLT Classification code 10001896 Term: Alzheimer's disease

Intervention(s)

Product Name: AZD1446 30 mg capsules
Product Code: AZD1446
Pharmaceutical Form: Capsule, hard
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

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)

Secondary Objective: · 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

Main Objective: 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)

Secondary ID(s)

2009-015525-37-HU

D1950C00006