| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild Alzheimer’s disease (AD) and amnestic mild cognitive impairment (amnestic MCI) |
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| 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 | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
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| 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 |
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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 assess AQW051 as a cognitive enhancer, as measured by selected tests (PAL, SWM, RVP) from the CANTAB computerized cognitive test battery, in patients with findings consistent with mild Alzheimer’s disease (AD) or amnestic mild cognitive impairment (amnestic MCI). |
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| E.2.2 | Secondary objectives of the trial |
• To explore effects of AQW051 on other cognitive functions not assessed by the primary measures (CANTAB tests PRM, CRT, GNT)
• To explore the safety and tolerability of AQW051 in patients with findings consistent with mild AD or amnestic MCI
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to participate, patients must:
1. Be willing and able to give written informed consent
2. Meet the following diagnostic criteria for either amnestic mild cognitive impairment (amnestic MCI) or mild Alzheimer’s Disease (AD): see full details in protocol
3. Be able to perform the Motor Control Task of the CANTAB computerized cognitive test battery
4. Have had a structural brain scan within the last 6 months prior to randomization that indicates no other underlying disease, in particular no evidence for vascular pathology except for normal age-related white matter/incidental white matter changes which is normal for this age group.
5. Have a score < 7 in the Hachinski ischemic index
6. Have daily contact with a primary caregiver/partner
7. Be aged 55 – 85 years
8. Have had no treatment with cholinesterase inhibitors within the last 3 months prior to randomization (Note: Treatment with memantine an NMDA receptor antagonist, is allowed)
9. Have sufficiently stable overall health, as determined by the Investigator. The regular intake of concomitant drugs including memantine, thyroxine, paracetamol, low-dose NSAR, lipid-lowering drugs, antihypertensive drugs, alpha blockers for symptoms of prostate hypertrophy, vitamins and dietary supplements without caffeine and nicotinic acid will be allowed, if the patient is on stable treatment for at least 3 months. Hormone replacement therapy will be allowed if the patient is on stable treatment for at least 1 month. If the patient takes more than one concomitant medication, it is at the Investigator’s discretion to decide about the patient’s eligibility, depending on the nature of the concomitant medications and the patient’s overall health. (See Appendix 3 for a list of medications and food that are not allowed during the study.)
10. Female patients must be surgically sterilized or postmenopausal. Surgical sterilization must have occurred at least 6 months prior to screening. Menopausal women must have no regular menstrual bleeding for at least 1 year prior to screening and serum FSH level of > 40 IU/L. However, depending on concomitant medication (hormone replacement) and age, women with a lower FSH level might be eligible upon case-by-case consideration by the Investigator (e.g., if there is evidence of non-child-bearing potential from the medical history or if a serum pregnancy test is performed at both screening and at the end of the study).
11. Male subjects must agree to refrain from fathering a child in the 3 months following last study drug administration.
12. At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed after the patient has rested for at least three (3) minutes in the supine position and again when required after three (3) minutes in the standing position.
Vital signs should be within the following ranges:
oral body temperature between 35.0-37.5°C
systolic blood pressure, 90 - ≤160 mm Hg
diastolic blood pressure, 50 - <95 mm Hg
pulse rate, 50-100 bpm
When blood pressure and pulse will be taken again after 3 minutes standing, there shall be no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in diastolic blood pressure and increase in heart rate (>20 bpm) associated with clinical manifestation of postural hypotension. All blood pressure measurements at other time-points should be assessed with the patient seated, unless stated otherwise in the protocol design and utilizing the same arm for each determination.
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| E.4 | Principal exclusion criteria |
In order to participate, patients must not:
• Have had investigational drug treatment within 4 weeks prior to screening (or longer if mandated by local health authority guidelines)
• Have had immune therapy targeting Alzheimer beta amyloid within the last 12 months
• Be institutionalized
• Have any disability that may prevent completion of all study requirements (e.g., blindness, deafness, or communication difficulty)
• Report use of tobacco products in the previous 3 months or have a urine cotinine level greater than 500 ng/ml
• Have used any new prescription drugs within 4 weeks prior to dosing or have used any new over-the-counter (OTC) medication (e.g., herbal supplements) within 2 weeks prior to dosing. (Note the exception of concomitant drugs on stable treatment for at least 3 months, as outlined in the inclusion criteria.) See Appendix 3 for a list of medications and food that are not allowed during the study.
• Use any of the medications listed in Appendix 3 unless the medication can be safely stopped and subjects are off this medication for at least 4 weeks before entering the trial
• Have used any CNS-active drug or anticholinergic drug during the previous 3 months (including cholinesterase inhibitors)
• Have used any drug or treatment known to cause major organ system toxicity during the previous 3 months
• Have donated or lost ≥ 400 ml of blood within 8 weeks prior to first dosing (or longer if required by local regulation)
• Have had any significant illness within 2 weeks prior to dosing
• Have a past medical history of clinically significant ECG abnormalities or a family history (grandparents, parents, and siblings) of prolonged QT-interval syndrome
• Have a current diagnosis of any of the following:
• Clinically significant cardiac arrhythmia derived from ECG
• Clinically significant cardiovascular disease
• Major Depression or any other DSM-IV, Axis 1 diagnosis that may interfere with the evaluation of response to study medication, including other primary neurodegenerative dementia, schizophrenia, or bipolar disorder.
• Positive hepatitis B surface antigen (HBsAg) or hepatitis C test result
• Have a history or current diagnosis of any of the following:
• Autonomic dysfunction (e.g., history of fainting, orthostatic hypotension, or sinus arrhythmia)
• Clinically significant acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated)
• Clinically significant drug allergy or history of atopic allergy (asthma, urticaria, or eczematous dermatitis)
• Hypersensitivity to the study drug, or drugs similar to the study drug
• Cerebrovascular disease (e.g., stroke, transient ischemic attacks, or aneurysms)
• Seizure disorder
• Immunodeficiency diseases, including a positive HIV test result (ELISA and Western blot)
• Drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations
• Have any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in case of participation in the study. The investigator should be guided by evidence of any of the following:
• History of inflammatory bowel syndrome, gastritis, ulcers, or gastrointestinal or rectal bleeding
• History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
• History or presence of impaired renal function, as indicated by clinically significant creatinine or BUN/Urea, or abnormal urinary constituents (e.g., albuminuria)
• Evidence of urinary obstruction or difficulty in voiding
• White blood cell count within the range of 3,000 to 11,000 /µl or platelets < 100,000 /µl
• History or clinical evidence of pancreatic injury or pancreatitis
• Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as SGOT, SGPT, GGT, alkaline phosphatase, or serum bilirubin. The following limits should be observed:
• SGPT must not exceed the ULN by more than 50%
• GT and alkaline phosphatase must not exceed twice the ULN
• Serum bilirubin should not exceed 27 µmol/L (1.6 mg/dl). If the total bilirubin concentration is increased above 1.5 times the ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary pharmacodynamic/efficacy assessments:
• CANTAB computerized cognitive test battery consisting of Paired Associates Learning (PAL), Spatial Working Memory (SWM), Rapid Visual Information Processing (RVP), Pattern Recognition Memory (PRM), Choice Reaction Time (CRT) and Graded Naming Test-Revised (GNT) will be administered on Day 28 (2 hours after last dosing). The PAL and RVP task will also be administered at baseline and on Day 1. In addition the RVP will be administered at each weekly visit (Days 8, 15 and 22) 2 hours after dosing.
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
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