Efficacy Study of a ZT-1 Implant in Patients Suffering From Alzheimer's Disease

This is a multicenter, randomised, double-blind, double-dummy, oral donepezil controlled study on the safety and efficacy of repeated monthly s.c. injections of a sustained-release implant of ZT 1 in patients with moderate Alzheimer's Disease.

The study enrolls patients aged >50 years, with moderate AD with a MMSE score at study screening ≥14 and ≤22. The study aims to recruit 128 patients.

The study is divided into 3 periods:

• A screening period
• A 6-month treatment period, consisting of one month of titration with an oral medication and 5 months of treatment with an implant administered under the skin every 4 weeks. Oral treatment will be maintained throughout the treatment phase
• A 2 week follow-up period.

Patients will be randomized in a 1:1 ratio to one of 2 groups: the ZT-1 (investigational product) treatment group or the donepezil (active comparator) treatment group.

The study comprises a total of 11 visits including screening and follow-up. An additional visit for PK/PD assessment is scheduled in about 10% of patients.

Inclusion criteria

• Presence of moderately severe probable AD, diagnosed according to the DSM-IV and the NINCDS-ADRDA criteria;
• MMSE score ≥ 14 and ≤ 22;
• Male/female patient aged > 50 years; female patients should be of no child-bearing potential or postmenopausal (at least one year after last menses);
• Body mass index (BMI) between 18 and 29 kg/m2 inclusive;
• Has a caregiver, is living at home or in an assisted living facility, is able to attend ambulatory study visits;
• Naïve to donepezil;
• Has discontinued another AChEI and/or memantine at least 3 months prior to study visit 2 (Day 1);
• Has a CT or MRI scan excluding another structural brain disease and supporting diagnosis of AD; CT or MRI scan must have been performed within 6 months prior to study visit 2 (Day 1, baseline);
• Fluent in English (mother tongue or working language);
• Able to communicate well with the Investigator;
• Physically able to carry out functional tasks;
• Has given written informed consent together with the caregiver.

Exclusion criteria

• Presence of any disabling, severe or life-threatening disease (cardiac, respiratory, gastro-intestinal, neurological, epileptic, psychiatric, infectious, bone, endocrinologic);
• Inability to discontinue at least 2 weeks prior to visit 2 (Day 1) (or within 5 drug half-lives, whichever is longer) any medication listed as prohibited;
• Proven or clinically suspected other type of dementia such as vascular dementia, post-traumatic dementia, fronto-temporal dementia, dementia associated with Parkinson's Disease, infectious disease HIV, syphilis), folate or vitamin B12 deficiency, hypothyroidism etc.;
• Significant liver impairment with ASAT, ALAT >=3x the upper normal limit at screening;
• Significant kidney impairment with serum creatinine >=2x the upper normal limit at screening;
• Presence of cardiac rhythm disorder, in particular bradycardia (< 60 bpm), conduction abnormalities such as AV block; presence of active ischaemia (such as unstable angina pectoris) or recent myocardial infarction, QT interval ≥ 450 msec at screening, QRS complex ≥ 110 msec at screening (ECG must be within normal limits at screening);
• Uncontrolled arterial hypertension i.e. patients with systolic blood pressure (BP) >=160 mmHg and/or diastolic >=100 mmHg, at screening despite regular medication;
• Uncontrolled arterial hypotension, i.e. patients with systolic BP ≤ 100 mmHg and/or presenting a fall of systolic BP ≥ 20 mmHg or a fall of diastolic BP >=10 mmHg after the 2 min Schellong test at screening;
• Any concomitant disorder or resultant therapy that is likely to interfere with patient compliance or his/her participation to the study;
• Participation in another study with an experimental drug within 3 months before study visit 2 (Day 1, baseline) or within 5 drug half-lives of the investigational drug (whichever is the longer);
• Known peripheral cholinergic intolerance, i.e. with previously prescribed AChEI(s);
• Known hypersensitivity to any of the test materials or related compounds, including lactose, present in the donepezil and placebo capsules;
• Known active use of recreational drug or alcohol dependence, current alcohol abuse;
• Inability to comply fully with the protocol;
• Patients who, in the opinion of the Investigator, are considered unsuitable for any other reason.