Official Title: “A Randomised, Double-Blind, Double-Dummy, Oral Donepezil Controlled Study on the Safety and Efficacy of Repeated Monthly Subcutaneous Injections of a Sustained-Release Implant of ZT 1 in Patients With Moderate Alzheimer's Disease”

Alzheimer's disease is characterised by memory loss and difficulties with thinking. These problems may be due to a deficiency in a brain chemical called acetylcholine. Acetylcholine helps transmit messages between nerve cells. Acetylcholine is degraded by an enzyme called "acetylcholinesterase". ZT-1 is a new drug derived from a plant extract already used in China for memory disorders, which blocks the action of the enzyme and restores adequate levels of acetylcholine.

This study will test the safety and efficacy of ZT-1 in the treatment of patients with Alzheimer's disease.

BRAINz stands for Better Recollection for Alzheimer's patients with the Implant of Zt-1.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2008

This is a 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 will enroll patients aged >50 years, with moderate AD, diagnosed according to the DSM-IV and NINCDS-ARDRA criteria with a MMSE score at study screening ≥14 and ≤22. 128 patients will be enrolled in 20-25 centres.

This study is divided into 3 periods:

1. A screening period that should not exceed 28 days

2. 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

3. 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.

Intervention(s) in this Clinical Trial

• Drug: ZT-1
  • Patients in the ZT 1 treatment group will receive ZT 1 1 mg capsules administered p.o. daily during the first month of treatment, followed by ZT 1 implants (9 mg) administered s.c. during the second month of treatment, followed by ZT 1 implants (12 mg) administered s.c. every 4 weeks during months 3 to 6 of treatment. Patients in the ZT 1 treatment group will receive dummy donepezil capsules during months 2 to 6 of the treatment period.
• Drug: Donepezil
  • Patients in the donepezil treatment group will receive donepezil 5 mg capsules administered p.o. during the first month of treatment, followed by donepezil 10 mg/day during months 2 to 6 of the treatment period. Patients in the donepezil treatment group will also receive s.c. injections of dummy ZT 1 implants every 4 weeks during months 2 to 6 of the treatment period.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • ZT-1 (investigational product)
• Active Comparator: 2
  • Donepezil

Primary Measures

• Change in the MMSE score from baseline to week 25
  • Time Frame: baseline to week 25
    Safety Issue?: No

Secondary Measures

• Responder rate as defined by at least 2 points improvement in the MMSE score;
  • Time Frame: baseline to week 25
    Safety Issue?: No
• Change on the ADAS-Cog 11 items subscale;
  • Time Frame: baseline to week 25
    Safety Issue?: No
• Change in the NPI-Q;
  • Time Frame: baseline to week 25
    Safety Issue?: No
• Change on the IADL scale;
  • Time Frame: baseline to week 25
    Safety Issue?: No
• Patient's convenience questionnaire.
  • Time Frame: baseline to week 25
    Safety Issue?: No

Inclusion Criteria:

• 1. Presence of moderately severe probable AD, diagnosed according to the DSM-IV and the NINCDS-ADRDA criteria;
• 2. MMSE score ≥ 14 and ≤ 22;
• 3. Male/female patient aged > 50 years; female patients should be of no child-bearing potential or postmenopausal (at least one year after last menses);
• 4. Body mass index (BMI) between 18 and 29 kg/m2 inclusive;
• 5. Has a caregiver, is living at home or in an assisted living facility, is able to attend ambulatory study visits;
• 6. Naïve to donepezil;
• 7. Has discontinued another AChEI and/or memantine at least 3 months prior to study visit 2 (Day 1);
• 8. 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);
• 9. Fluent in English (mother tongue or working language);
• 10. Able to communicate well with the Investigator;
• 11. Physically able to carry out functional tasks;
• 12. Has given written informed consent together with the caregiver.

Exclusion Criteria:

• 1. Presence of any disabling, severe or life-threatening disease (cardiac, respiratory, gastro-intestinal, neurological, epileptic, psychiatric, infectious, bone, endocrinologic);
• 2. 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;
• 3. 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.;
• 4. Significant liver impairment with ASAT, ALAT >=3x the upper normal limit at screening;
• 5. Significant kidney impairment with serum creatinine >=2x the upper normal limit at screening;
• 6. 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);
• 7. Uncontrolled arterial hypertension i.e. patients with systolic blood pressure (BP)
• >=160 mmHg and/or diastolic >=100 mmHg, at screening despite regular medication;
• 8. 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;
• 9. Any concomitant disorder or resultant therapy that is likely to interfere with patient compliance or his/her participation to the study;
• 10. 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);
• 11. Known peripheral cholinergic intolerance, i.e. with previously prescribed AChEI(s);
• 12. Known hypersensitivity to any of the test materials or related compounds, including lactose, present in the donepezil and placebo capsules;
• 13. Known active use of recreational drug or alcohol dependence, current alcohol abuse;
• 14. Inability to comply fully with the protocol;
• 15. Patients who, in the opinion of the Investigator, are considered unsuitable for any other reason.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 50 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Debiopharm S.A.

Overall Clinical Trial Officials and Contacts

Emmanuel Tamches, MD Study Director Debiopharm SA  

Overall Contact: Genevieve Decosterd Kerhuel, PharmD +41 21 321 0111 gdecosterd@debiopharm.com

Information obtained from ClinicalTrials.gov on November 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00423228

Study ID Number: DEB-ZTSR-201

ClinicalTrials.gov Identifier: NCT00423228

Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration

Sponsor of the Study

International Contract Research Organisation representing the Sponsor and in charge of the monitoring of the Study.

Alzheimer's Disease Education and Referral (ADEAR) Center