| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
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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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
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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 determine the safety and tolerability of multiple, once-daily oral doses of CNP520 over 13 weeks in healthy elderly subjects. |
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| E.2.2 | Secondary objectives of the trial |
To assess the change from baseline of CSF Aβ concentrations (Aβ1-38; Aβ1-40; Aβ1-42) in healthy elderly subjects over 13 weeks treatment with CNP520 as compared to placebo.
To determine the CNP520 plasma PK and CSF concentrations of once-daily oral doses of CNP520 over 13 weeks in healthy elderly subjects. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed.
2. Male and postmenopausal female subjects aged 60 to 80 years, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
Sexually active males must use a condom during intercourse while taking drug and for at least 3 months after stopping investigational medication and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
3. Total MMSE score ≥25 for subjects with low educational attainment (12 or fewer years of education) or ≥27 for subjects with high educational attainment (13 or more years of education).
4. Ability to perform cognitive assessments (i.e. Cogstate battery as defined in the SOM).
5. Subjects must weigh at least 45 kg to participate in the study, and must have a body mass index (BMI) within the range of ≥18 to ≤34 kg/m2. BMI = Body weight (kg) / [Height (m2)].
6. Ability to communicate well with the investigator, to understand and comply with the requirements of the study. |
|
| E.4 | Principal exclusion criteria |
1. Use of other investigational drugs at the time of screening, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations.
2. History of hypersensitivity to BACE inhibitors.
3. Clinically significant ECG abnormalities as determined by single 12-lead ECGs and judged by the investigator.
4. Known family history or known presence of long QT syndrome or use of drugs known to prolong the QT interval unless it can be permanently discontinued from two weeks prior first dosing until study completion.
5. Clinically significant abnormal vital sign data as judged by the investigator.
6. History of hypersensitivity or known allergy to local anesthetics.
7. History of malignancy of any organ system within the past 5 years except for localized tumors not requiring systemic chemo- or radiotherapy such as localized basal cell carcinoma of the skin or in-situ cervical cancer.
8. Pregnant or nursing women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
9. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or “yes” on any item of the Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious Behavior”, if this behavior occurred in the past 2 years.
10. History or presence of any clinically significant disease of any major system organ class including cardiovascular, pulmonary, metabolic, endocrine, immunological or renal diseases which has not resolved within two weeks prior to initial dosing.
11. Heavy smokers.
12. Use of drugs known to be strong inhibitors or inducers of CYP3A4 and narrow-therapeutic index drugs known to be primarily metabolized by CYP2C or CYP3A isoenzymes within four weeks prior to initial dosing or within at least 5 half-lives prior to dosing, whichever longest.
13. Donation or loss of 450mL or more of blood within eight weeks prior to initial dosing, or longer if required by local regulation.
14. Plasma donation (>200mL) within 7 days prior to first dosing.
15. History within the last two years of autonomic dysfunction (e.g. recurrent episodes of fainting, palpitations etc.).
16. History within the past 2 years or presence of clinically significant neurological or psychiatric disorders including seizures, dementia, head trauma, schizophrenia, major depression, pseudotumor cerebri, bipolar disorder or demyelinating diseases.
17. Subject is mentally or legally incapacitated or has significant emotional problems in the opinion of the investigator.
18. Any abnormalities of laboratory values that are considered as clinically significant per investigator’s judgment.
19. Clinically significant thrombocytopenia or abnormal coagulation parameters including but not limited to prothrombin time and activated partial thromboplastin time.
20. Any medical condition that might lead to or is associated with any cognitive deficit including clinically relevant abnormality of thyroid function, vitamin B12 or folate deficiency, post-traumatic conditions, Huntington’s disease, Parkinson’s disease, Lyme disease or syphilis as reported by the subject.
21. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays.
22. History or presence of conditions that may increase the susceptibility to drug-induced liver injury (DILI) or that may confound the ability to diagnose DILI.
23. History or presence of severely impaired renal function as indicated by an estimated glomerular filtration rate <30mL/min. Evidence for urinary obstruction or difficulty in voiding.
24. Current dermatological infection, inflammation or other relevant skin alteration at the site of lumbar puncture.
25. Past or current history of macula degeneration, drusen deposits in retinal pigment epithelium, retina degeneration or mitochondrial diseases/dysfunction as reported by the subject.
26. History of back surgery (with the exception of microdiscectomy or laminectomy over 1 level) as reported by the subject.
27. Subjects with spinal deformities or other spinal condition that in the judgment of the investigator would preclude a lumbar puncture.
28. Intake of anticoagulant drugs including vitamin K antagonists within four weeks prior to initial dosing.
29. Clinically significant infection or vaccination with live-attenuated vaccines in the 3 months before enrollment (except for influenza).
30. Any disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, communication difficulty).
31. History of immunodeficiency diseases, including a positive HIV test result.
32. A positive Hepatitis B surface antigen or Hepatitis C test result.
33. Any elevation ≥1.5x ULN of more than one parameter of ALT, AST, γ-GT, alkaline phosphatase or total bilirubin. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To determine the safety and tolerability of multiple, once-daily oral doses of CNP520 over 13 weeks in healthy elderly subjects (Safety: ECG, vital signs and laboratory data; assessment of cognitive function; dermatological assessment and visual field/acuity testing. Tolerability: Adverse event data). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety and tolerability assessments will be performed at baseline (randomization) and then every 2 weeks until week 12, at week 13 (last drug administration), and at week 17 (study completion visit). |
|
| E.5.2 | Secondary end point(s) |
To assess the change from baseline of CSF Aβ concentrations (Aβ1-38; Aβ1-40; Aβ1-42) in healthy elderly subjects over 13 weeks treatment with CNP520 as compared to placebo.
To determine the CNP520 plasma PK and CSF concentrations of once daily oral doses of CNP520 over 13 weeks in healthy elderly subjects. (Plasma PK parameters: Day 1: Cmax, Tmax, AUClast and if possible T1/2, AUCinf, Vz/F and CL/F; Day 91: Cmax,ss, Tmax,ss, AUClast,ss, AUCtau,ss, T1/2, Vz/F, CLss/F and Racc; Population PK analysis: PK results from current study will be pooled with other studies. CNP520 concentrations in CSF). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CSF Aβ concentration assessments will be performed at baseline and at week 13, as well as one time point in between, i.e. at week 2, 4, 6, 8 or 10.
Plasma PK and CSF concentration assessments will be performed at baseline and then every 2 weeks until week 12, at week 13, and at week 17. |
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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 | No |
| 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 | 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 6 |
| 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 | No |
| 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 |
| Belgium |
| Germany |
| Netherlands |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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