| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
|
| 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 evaluate the safety and tolerability of three escalated doses of NP031112 administered over 14 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
To explore the effect of treatment for 14 weeks with three doses of NP031112 on:
- cognition and
- depressive mood
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men and women (non-childbearing potential) with a diagnosis of probable Alzheimer’s disease according to the NINCDS-ADRDA clinical criteria.
2. Age 60 - 85 years (patients over 85 years could be included after a previous assessment by the investigator and in agreement with the sponsor)
3. MRI or CT-scan assessment within 12 months before baseline corroborating the clinical diagnosis (diffuse brain atrophy predominating in medial temporal regions) and excluding other potential causes of dementia, especially cerebrovascular lesions (see exclusion criteria, number 3).
4. Mild to moderate stage of Alzheimer’s disease according to MMSE 16-26.
5. Modified Hachinski ischemic score equal to or below 4.
6. Geriatric Depression Scale below or equal 7.
7. Female patients must be either surgically sterilized or at least 1 year postmenopausal (confirmed by FSH >20, for women not surgically sterilized).
8. A caregiver/study nurse is available and is living in the same household, or interacts with the patient for >4 hours at least 4 times a week.
9. Patients living at home or old people’s home.
10. General health status acceptable for a participation in a 4 months clinical trial.
11. Ability to swallow 100 ml of water suspension.
12. SSRIs as antidepressants are permitted after maintenance of dose for two months prior to baseline evaluation.
13. No regular treatment with benzodiazepines. Lorazepam 1 mg or medication containing opioids for anxiety, sleep induction or pain will be allowed only as occasional treatment, but not within two days before cognitive assessments.
14. No history of treatment with Warfarin or Digoxin will be allowed within 3 months before screening.
15. Other drugs metabolized by the CYP3A4 with wide therapeutic window are permitted if their dose and regimen are stable and well tolerated for at least 3 months prior to screening.
16. Stable pharmacological treatment of any other chronic condition for at least one month prior to screening.
17. No regular/chronic intake of medications acting on central nervous system or any non-steroid anti-inflammatory agents.
18. Treatment with a stable and well tolerated dose of one of the approved Acetylcholinesterase-Inhibitors (e.g. Donepezil) for at least 2 months prior to baseline evaluations. Dosage of Acetylcholine-esterase inhibitors should not be increased during the ongoing study.
19. No history of treatment with Memantine within 3 months prior to baseline evaluation.
20. Signed informed consent by patient (and legal representative if applicable) prior to the initiation of any study specific procedure
|
|
| E.4 | Principal exclusion criteria |
1. Failure to perform screening or baseline examinations.
2. Hospitalization or change of chronic concomitant medication within 1 month prior to screening period.
3. Clinical, laboratory or neuroimaging findings consistent with:
• other primary degenerative dementia, (dementia with Lewy bodies, frontotemporal dementia, Huntington’s disease, Jacob-Creutzfeld Disease, Down’s syndrome, etc)
• other neurodegenerative condition (Parkinson’s disease, amyotrophic lateral sclerosis, etc.)
• cerebrovascular disease (major infarct, one strategic or multiple lacunar infarcts, extensive white matter lesions)
• other central nervous system diseases (severe head trauma, tumors, subdural haematoma or other space occupying processes, etc.)
• seizure disorder
• other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc.)
4. A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder.
5. Clinically significant, advanced or unstable disease that may interfere with evaluations, may bias the assessment of the clinical or mental status of the patient or put the patient at special risk, such as:
• chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency
• respiratory insufficiency
• renal insufficiency (serum creatinine >2mg/dl)
• heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within 6 months before screening)
• bradycardia (heart beat <50/min.) or tachycardia (heart beat >95/min.)
• hypertension or hypotension requiring treatment with more than 2 drugs
• AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males >450 and females >470 msec)
• uncontrolled diabetes
• malignant tumors within the last 5 years except skin malignancies (other than melanoma) or indolent prostate cancer
• metastases
6. Disability that may prevent the subject from completing all study requirements (e.g., blindness, deafness, severe language difficulty, etc.)
7. Women who are fertile and of child bearing potential.
8. Anticoagulant treatment with heparin i.v.
9. Chronic drug intake of:
• drugs metabolized by the CYP3A4 with narrow therapeutic window (i.e. warfarin, digoxin, …).
• antidepressants (other than SSRIs), benzodiazepines, neuroleptics or major sedatives
• antiepileptics
• anticholinergics
• nootropics
• centrally active anti-hypertensive drugs (clonidine, -methyl dopa, guanidine, guanfacine, …)
• opioid containing analgesics
• non steroid anti-inflammatory agents (regular intake!), cortico-steroids or immunosuppressants
• lithium or other inhibitor of GSK3 enzyme
10. Suspected or known drug or alcohol abuse.
11. Suspected or known allergy to any components of the study treatments.
12. Enrollment in another investigational study or intake of investigational drug within the previous 3 months.
13. Any condition which in the opinion of the investigator makes the patient unsuitable for inclusion.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Adverse events
- Liver Function Tests (total bilirubin, ALT, AST and gamma-GT)
- Hematology: erythrocytes, hemoglobin, hematocrit, MCH, MCV, leucocytes, neutrophils, eosinophils, basophils, lymphocytes, monocytes and thrombocytes.
- Clinical chemistry: total bilirubin, ALT, AST, LDH, alkaline phosphatase, gamma-GT, creatinine, BUN, uric acid, CK, Na, K, phosphate, calcium, albumin, total cholesterol, triglycerides, glucose and prothrombin time.
- Urine laboratory: pH, glucose, albumin, ketones, red and white blood cells.
- Physical exam (including the weight)
- Vital signs
- Triplicate 12-lead ECG |
|
| 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 | No |
| 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 | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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