E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
moderate Alzheimer disease |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10001897 |
E.1.2 | Term | Alzheimer's disease (incl subtypes) |
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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 the efficacy of the ZT-1 implant in improving cognitive function, behavioural and overall outcomes, compared to oral daily doses of donepezil
To assess the safety of the ZT-1 implant, compared to oral daily doses of donepezil |
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E.2.2 | Secondary objectives of the trial |
To measure plasma concentrations of ZT-1, its active metabolite Hup A and other potentially related metabolites;
To measure the inhibition of RBC AChE activity.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 computed tomographic (CT) or magnetic resonance imaging (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 visit 2 (Day 1); 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.
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E.4 | Principal 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: a. All “cholinergic” medications, other than AChEI, including anticholinergics, cholinomimetics; antihistamines; sympaticomimetics; b. Muscle relaxants such as suxamethonium; c. Any psychotropic drugs except those deemed necessary by the Investigator (i.e. emergency use); 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 (human immunodeficiency virus [HIV], syphilis), folate or vitamin B12 deficiency, hypothyroidism etc.; 4. Significant liver impairment with aspartate aminotransferase (ASAT), alanine aminotransferase (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 rythm 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 minutes (min) Schellong test at screening (see Appendix A: Schellong Test); 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) 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy endpoints: Primary endpoint Change from baseline in the MMSE score to week 25 [visit 11 (Day 169)]. Secondary endpoints at week 25 [visit 11 (Day 169)] 1. Responder rate as defined by at least 2 points improvement in the MMSE score; 2. Change on the ADAS-cog 11 items subscale; 3. Change in the NPI-Q; 4. Change on the IADL scale; 5. Patient’s convenience questionnaire.
Safety endpoints: 1. Incidence of AEs; 2. Change in vital signs; 3. Change in standard haematology, biochemistry and urinalysis parameters; 4. Change in 12-lead ECG (RR, PR, QRS, QT, and QTc intervals).
Pharmacokinetic/Pharmacodynamic endpoints: 1. Maximum plasma concentration (Cmax) of ZT 1, its active metabolite Hup A and potentially other related metabolites; 2. Maximum inhibition (Imax) of RBC AChE activity.
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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 | Yes |
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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | No |
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 | Yes |
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |