E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 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 | 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 demonstrate the effect of CNP520 vs placebo on time to diagnosis of MCI due to AD or dementia due to AD, whichever occurs first during the course of the study.
- To demonstrate the effect of CNP520 vs placebo on cognition using APCC. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objective:
- To demonstrate the effects of CNP520 vs placebo on global clinical status.
Secondary objectives:
- To demonstrate the safety and tolerability of CNP520 vs placebo.
- To demonstrate the effects of CNP520 vs placebo on cognition using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
- To demonstrate the effects of CNP520 vs placebo on function.
- To demonstrate the effects of CNP520 vs placebo on Magnetic Resonance Imaging (MRI) measures suggestive of cerebral amyloid angiopathy (CAA).
- To demonstrate the effects of CNP520 vs placebo on brain atrophy.
- To demonstrate the effects of CNP520 vs placebo on AD-related biomarkers. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Screening part I: Participants eligible for inclusion must fulfill all of the
following criteria prior to scheduling the genetic disclosure.
1. Written informed consent must be obtained before any assessment is
performed as part of the study, including consent to receive disclosure of
their risk estimates to develop clinical symptoms of AD based on their
APOE genotype and, if HTs, with evidence of elevated brain amyloid.
2. Male or female, age 60-75 years inclusive, at the time of signing the
informed consent. To ensure that no more than 20% of participants in the age group 60-64 years are randomized across the whole recruitment
period, a site level process will be implemented.
3. Females must be considered post-menopausal and not of child bearing
potential i.e. they have had 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. history of
vasomotor symptoms), or have had surgical bilateral oophorectomy
(with or without hysterectomy), total hysterectomy, or tubal ligation.
4. Intellectually, visually and auditorily capable, fluent in, and able to
read, the language in which study assessments are administered (e.g.
completion of at least 6 years of regular schooling or sustained
employment or equivalent local level of knowledge).
5. Mini-Mental State Examination total score ≥24.
6. Willing to have a study partner throughout the study.
Screening part II: Participants eligible for inclusion must fulfill all of the
following criteria prior to randomization based on the results from the
screening test procedures.
7. Carrier of at least one ε4 allele of the APOE gene: HMs with elevated
or not elevated brain amyloid OR HTs with elevated brain amyloid (as
measured in CSF collected via lumbar puncture or by amyloid PET
imaging).
Note: In cases where both lumbar puncture (CSF) amyloid and amyloid
PET imaging tests are performed, at least one should be indicative of
elevated brain amyloid.
8. Cognitively unimpaired at screening visit as defined by: Score of 85 or
greater on the RBANS delayed memory index score AND CDR global
score of 0 with two special exceptions: a) If the RBANS delayed memory
index score is between 70 and 84 (inclusive) AND the global CDR = 0,
the participant may be allowed to continue ONLY if the investigator
judges that cognition is unimpaired following review of the
MCI/dementia criteria; b) If the global CDR score = 0.5 AND the RBANS
delayed memory index score is 85 or greater, the participant may be
allowed to continue ONLY if the investigator judges that cognition is
unimpaired following review of the MCI/dementia criteria.
9. Having a study partner who agrees to participate in the study and who
is intellectually, visually, and auditorily capable, and fluent in, and able
to read, the language in which study assessments are administered.
Additionally, the study partner must be capable of and willing to: a)
Accompany the participant to visits that requires the input of the study
partner; b) Meet the definition of a "study partner".
Other protocol defined inclusion criteria may apply. |
|
E.4 | Principal exclusion criteria |
Screening part I: Participants will be excluded if they fulfill any of the
following criteria prior to scheduling the genetic disclosure.
1. Current medical or neurological condition that might impact cognition
or performance on cognitive assessments e.g. MCI, dementia,
Huntington's or Parkinson's disease etc.
2. Advanced, severe progressive or unstable disease that may interfere
with the safety, tolerability and study assessments, or put the
participant at special risk e.g. active hepatitis, HIV infection, severe
renal impairment, severe hepatic impairment etc.
3. History of malignancy of any organ system, treated or untreated,
within the past 60 months, regardless of whether there is evidence of
local recurrence or metastases. However, localized nonmalignant tumors
not requiring systemic chemo- or radio-therapy, localized basal or
squamous cell carcinoma of the skin, in-situ cervical cancer are
permitted.
4. Current treatment with Cholinesterase Inhibitors and/or another AD
treatment.
5. Clinically relevant depigmenting or hypopigmenting conditions or
active/history of chronic urticaria in the past year.
6. Score "yes" on item 4 or 5 of the Suicidal Ideation section of the
eCSSRS patient-reported outcome, 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 prior to screening.
7. Lacking psychological readiness to receive APOE genotype/amyloid
status results, as assessed based on investigator's judgement supported
by the pre-disclosure rating scales: Geriatric Depression Scale total score
>6; Six Item Subset Inventory of the modified State Trait Anxiety
Inventory total score >17.
8. Use of other investigational drugs prior to screening until: Small
molecules: after 5 half-lives, or within 30 days until the expected
pharmacodynamic effect has returned to baseline, whichever is longer;
Biologicals: blood concentration has returned to baseline (or below
serological responder threshold) for antibodies induced by active
immunotherapy; or 5 half-lives for monoclonal antibodies or other
biologicals.
9. Treatment
a) in the 4 weeks prior to randomization with any drug or treatment
known for the potential to cause major organ system toxicity i.e. drugs
that may require periodic safety monitoring of a specific organ or body
fluid.
b) in the 4 weeks prior to randomization and/or current treatment with
any CNS active drugs with the exceptions.
10. Current chronic treatment (>3 months) with: Strong CYP3A4
inducers or inhibitors; Drugs with a narrow therapeutic index known to
be primarily metabolized by CYP2C or CYP3A isoenzymes and sensitive
P-gp substrates.
11. Violations of concomitant medication restrictions.
12. Donation or loss of 400 mL or more of blood within 8 weeks prior to
screening blood sampling and/or lumbar puncture if applicable.
13. Contraindication or intolerance to MRI investigations.
Screening part II: Participants fulfilling any of the following criteria
based on results from the screening test procedures will be excluded.
14. A positive drug screen, if, in the investigator's opinion, this is due to
drug abuse. Participants with a positive drug screen not believed to be
related to drug abuse can be re-screened.
15. Previous participation in a CNP520 study with >3-month exposure to
active treatment.
16. Significantly abnormal laboratory results at screening, meeting the
exclusionary alert values specified in the Laboratory Manual. If, in the
opinion of the investigator, an abnormal finding is the result of a
temporary condition, the laboratory test can be repeated.
17. Current significant ECG findings from central reader that are
assessed as clinically significant by the investigator. QTc interval >500
ms is exclusionary.
18. Brain MRI results from the central reading showing findings
unrelated to AD that, in the opinion of the investigator might be a
leading cause of future cognitive decline, might pose a risk to the
participant, or might confound MRI assessment for safety monitoring
(e.g. extensive white matter lesions, stroke, cerebrovascular disease as
evidenced by multiple lacunar infarcts ≤20 mm or single infarct >20 mm,
evidence of cerebral contusion etc.).
19. If PET scans are scheduled for this participant: Total dosimetry
above the acceptable exposure in the country when combining the
previous or planned Nuclear Medicine Radiology exposure and the
scheduled study PET scan(s).
20. If CSF sampling is scheduled for this participant: Contraindication to
lumbar puncture e.g. low platelet count, abnormal prothrombin time
international normalized ratio, history of back surgery (except
microdiscectomy or laminectomy over one level), signs or symptoms of
intracranial pressure etc.
Other protocol defined exclusion criteria may apply. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
- Time to the first event with event defined as the first confirmed diagnosis of MCI due to AD or dementia due to AD.
- Change from baseline to month 60 in APCC score. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Baseline to month 60.
- Baseline to month 60. |
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E.5.2 | Secondary end point(s) |
- Change from baseline to month 60 in Clinical Dementia Rating Scale - Sum of Boxes (CDRSOB) score.
- Frequencies, changes from baseline, Kaplan-Meyer estimates when applicable of: Adverse events; Skin events based on a centralized dermatological monitoring; Safety findings from brain structural MRI central reader; Laboratory tests; Vital signs; ECG findings; Prospective suicidality assessment (ideation and behavior) from eC-SSRS.
- Change from baseline to month 60 in total RBANS score and individual neurocognitive domain index scores.
- Change from baseline to month 60 in total score of the Everyday Cognitive (ECog) scale: ECogsubject and ECog-informant.
- Number, intensity and location of microhemorrhages and white matter hyperintensities using the Wahlund scale, both as assessed by central MRI reader.
- Change from baseline to month 60 on volume of brain regions as measured by volumetric MRI.
- Change from baseline to 24 and 60 months on: amyloid deposition as measured by standardized uptake ratio (SUVR) of radiotracer positron emission tomography (PET) scan; CSF levels of Aβ40, Aβ42; neurodegeneration as measured by CSF levels of total tau and
phosphorylated tau. Collected only in participants who consented to additional voluntary procedures. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Baseline to month 60.
- Baseline to month 60.
- Baseline to month 60.
- Baseline to month 60.
- Baseline to month 60.
- Baseline to month 60.
- Baseline to month 24 and 60. |
|
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 | 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 | 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) | Yes |
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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Argentina |
Australia |
Canada |
Chile |
China |
Israel |
Japan |
Korea, Republic of |
Mexico |
Singapore |
South Africa |
Taiwan |
United States |
Belgium |
Finland |
France |
Germany |
Iceland |
Italy |
Netherlands |
Portugal |
Spain |
Switzerland |
United Kingdom |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |