E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to moderate Alzheimer's disease |
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E.1.1.1 | Medical condition in easily understood language |
Mild to moderate Alzheimer's disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 100000014713 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066571 |
E.1.2 | Term | Progression of Alzheimer's disease |
E.1.2 | System Organ Class | 100000014713 |
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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 investigate the safety and tolerability of 200mg bid and 400mg bid doses of LM11A-31-BHS (free base) administered for a period of 26 weeks in comparison to placebo. Safety will be assessed through adverse event reporting, clinical laboratory, ECG and a standard range of patient physical evaluations including a suicide severity rating scale (C-SSRS).
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E.2.2 | Secondary objectives of the trial |
Exploratory investigation of relevant biomarkers for AD and drug mechanism including regional brain glucose metabolism (18F-FDG-PET) and CSF measures. The assessment of exploratory clinical endpoints including a composite of the specific cognitive tests performed (the NTB composite standardized Z score). The investigation of the pharmacokinetics of 200mg bid and 400mg bid doses of LM11A-31-BHS (free base) administered for a period of 26 weeks. PK parameters for LM11A-31 and its aminoethyl morpholine metabolite will be estimated using noncompartmental analysis (NCA).
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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 Alzheimer’s disease according to McKhann (2011) criteria 2. Age 50 - 85 years 3. MRI or CT assessment within six months before baseline, corroborating the clinical diagnosis of AD and excluding other potential causes of dementia, especially cerebrovascular lesions (see exclusion criteria, number 3) 4. CSF AD specific biomarker profile; positive, defined as CSF Aβ42 <530 ng l−1 together with either of T-tau>350 ng l−1 or p-tau >60 ng −1 5. Mild to moderate stage of Alzheimer’s disease according to MMSE ≥18 and ≤26 6. Absence of major depressive disease according to GDS of < 5 7. Modified Hachinski Ischemic Scale ≤4 8. Formal education for eight or more years 9. Previous decline in cognition for more than six months as documented in patient medical records 10. A caregiver available and living in the same household or interacting with the patient a sufficient time each week and available if necessary to assure administration of drug 11. Patients living at home or nursing home setting without continuous nursing care 12. General health status acceptable for a participation in a 6-month clinical trial 13. Ability to swallow capsules 14. Stable pharmacological treatment of any other chronic condition for at least one month prior to screening 15. Stable treatment with one of the acetylcholinesterase inhibitors donepezil (Aricept ®), galantamine (Razadyne®), or rivastigmine (Exelon) or the partial NMDA receptor antagonist with memantine (Namenda®) at least 3-months before baseline Visit or Combination of both treatments mentioned above 16. No regular intake of prohibited medications as noted in Section 11.8. of the protocol 17. Signed informed consent by caregiver and patient prior to the initiation of any study specific procedure.
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E.4 | Principal exclusion criteria |
1. Failure to perform screening or baseline examinations 2. Hospitalization or change of chronic concomitant medication one month prior to screening or during screening period 3. Clinical, laboratory or neuro-imaging findings consistent with: • Other primary degenerative dementia, (dementia with Lewy bodies, fronto-temporal dementia, Huntington’s disease, Creutzfeldt-Jakob 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 > one quarter of the total white matter) • Other central nervous system diseases (severe head trauma, tumors, subdural hematoma 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 primary or secondary variable evaluations, and which 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 (ALT, AST, Gamma GT, alkaline phosphatase > 2.5 ULN) • Respiratory insufficiency • Renal insufficiency (serum creatinine >2mg/dl) or creatinine clearance ≤ 30 mL/min according to Cockcroft-Gault formula. In case of creatinine clearance ≤30mL/min, an alternative verification of the renal function must be completed using Cystatin C analysis. In case of normal level of Cystatin C, the patient can be included • Heart disease (myocardial infarction, unstable angina, heart failure, Cardiomyopathy within six months before screening) • Bradycardia (heart beat <50/min.) or tachycardia (heart beat >95/min.) • Hypertension (>180/95) or hypotension (<90/60) requiring treatment with more than three 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 defined by HbA1c >8.5 • Malignant tumors within the last five years except skin malignancies (other than melanoma) or indolent prostate cancer • Metastases 6. Disability that may prevent the patient from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.) 7. Women who are fertile and of childbearing potential 8. Chronic daily drug intake of ≥ 14 days or expected for ≥ 14 days: • Benzodiazepines, neuroleptics or major sedatives • Antiepileptics • Centrally active anti-hypertensive drugs (clonidine, l-methyl DOPA, guanidine, guanfacine, etc.) • Opioid containing analgesics 9. Nootropic drugs 10. Suspected or known drug or alcohol abuse, i.e. more than approximately 60 g alcohol (approximately 1 liter of beer or 0.5 liter of wine) per day indicated by elevated MCV significantly above normal value at screening 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 three months 13. Any condition, which, in the opinion of the investigator, makes the patient unsuitable for inclusion
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E.5 End points |
E.5.1 | Primary end point(s) |
All safety evaluations will be summarized as interval or categorical summaries as appropriate. The overall incidence of adverse events, together with the top three most frequently reported adverse events, will be analyzed using a binary logistic model to demonstrate differences between the treatment groups and placebo. The end points include alls Adverse events (AEs), Serious adverse events (SAEs), Clinical Diagnostics, Vital signs (blood pressure, heart rate, respiratory rate, body temperature), ECG, Laboratory assessment (hematology, biochemistry, coagulation, serology and urinalysis), Columbia-Suicide Severity Rating Scale (C-SSRS), MRI scans (analyzed by a central reader) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Changes between baseline and end of study visit (26 weeks) |
Unterschiede zwischen den Werten bei der Baseline und der letzten Visite (26. Woche) |
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E.5.2 | Secondary end point(s) |
All exploratory efficacy variables will be analyzed at the endpoint (Final visit). The analyses will involve the change from baseline in the NTB composite summary Z score calculated after 6 months (26 weeks) of treatment. This will involve an Analysis Of Covariance Variance (ANCOVA) model incorporating the baseline score and country as covariates.
Additional analyses will involve evaluation of the time course of treatment response over the treatment period, using a repeated measures mixed model Analysis of Covariance (ANCOVA) for evaluation. 18F-Pet Scan variables will be analyzed in a descriptive and exploratory manner. Categorical endpoints will be analyzed using a Cochran Mantel-Haenszel (CMH-row mean scores difference), chi-squared test or Logistic regression models (as appropriate). Exploratory/ Candidate Efficacy variables • CSF-Biomarkers (tau, ptau, Aβ40, Aβ42, AchE activity) • Regional brain glucose metabolism (18FDG-PET) • NTB: o Digit Span Test o Category Fluency Test o COWAT o Digit Symbol Substitution Test (DSST) • ADAS-cog 13 items • SPATIAL ORIENTATION AND LEARNING (Amunet) • Geriatric Depression Scale (GDS) • Clinical Global Impression Scale – Severity/Improvement (CGI-I/CGI-S)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Changes between baseline and end of study visit (26 weeks) |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
LM11A-31-BHS (unterschiedliche Dosis) |
LM11A-31-BHS (differnt dose) |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
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 | No |
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 | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |