A randomized, double-blind, placebo-controlled, two-cohort parallel group study to evaluate the efficacy of CAD106 and CNP520 in participants at risk for the onset of clinical symptoms of Alzheimer*s disease

Pre-screening Epoch and Genetic Disclosure Follow-up inclusion criteria1.
Written informed consent (Informed consent #1) obtained before any assessment
is performed, including consent to receive disclosure of their APOE genotype.
2. Male or female, age 60 to 75 years inclusive, at the time of signing the
informed consent #1 (same age restriction also applied at informed consent #2).
a. Once the cap of approximately 20% of total participants in the age group 60-
64 years is met, a restriction to this age group will apply.
3. Females must be considered post-menopausal and not of child bearing
potential. Confirmation will be obtained for those who continue on to the
Screening Epoch.
4. Mini-Mental State Examination (MMSE) total score * 24 (can be based on
documented result obtained i previous 3 months).
5. Psycholgical readiness to receive APOE genotype information based on
pre-disclosure rating scales:
a. Geriatric Depression Scale (GDS short form) total score *6.
If the score is between 7 and 10 (inclusive), the participant can only be
included based on investigator*s judgment assessing in particular the scores
of the questions:
i. Item 3: *Do you feel your life is empty?*
ii. Item 6: *Are you afraid that something bad is going to happen to you?*
iii. Item 12: *Do you feel pretty worthless the way you are now?*
iv. Item 14: *Do you feel your situation is hopeless?*
b. Six Item Subset Inventory of the STAI-AD total score *17.
If the score is 18 or 19, the participant can only be included based on the
investigator*s judgment.
6. Participant is fluent in, and able to read the language in which the study
are administered (e.g. completion of at least 6 years of regular schooling or
sustained employment).
7. Participant*s willingness to have a study partner for the Screening and
Treatment epoch.
Screening and Treatment Epoch inclusion criteriaParticipants eligible for
inclusion must fulfill all of the following criteria prior to randomization:
1. Written informed consent (Informed consent #2) for participation to the
Screening and Treatment Epochs (participant must still be between 60-75 years,
inclusive at the time of signing ICF #2; respectively 65-75 after reaching the
maximum of 20% in the ypunger age group 60-64).
2. Continue to meet all eligibility criteria from Pre-screening Epoch and
Genetic Disclosure Follow-up, as confirmed by the review of the medical records
by the Investigator.
3. Homozygous APOE4 genotype.
4. Cognitively unimpaired as defined by:
* At the screening visit, score of 85 or greater on the RBANS delayed memory
index score
AND
* CDR global score of 0
with two exceptions:
­ If the RBANS delayed memory index score is between 70 and 84 (inclusive) AND
the global CDR score <= 0, the participant may be allowed to continue ONLY if
the Investigator judges that cognition is unimpaired following review of the
MCI/dementia criteria.
­ 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.I
5. 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. 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
before the amyloid PET.
Other protocol defined inclusion criteria may apply.
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Pre-screening Epoch and Genetic Disclosure Follow-up exclusion criteria1. Any
disability that may prevent the participants from completing all study
requirements (e.g., blindness, deafness, severe language difficulty).
2. Current medical or neurological condition that might impact cognition or
performance on cognitive assessments.
3. Advanced, severe progressive or unstable disease that may interfere with the
safety, tolerability and study assessments, or put the participant at special
risk.
4. 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, localized vulvar carcinoma and localized
prostate carcinoma with no progression over the past two years are permitted.
5. History of hypersensitivity to any of the investigational drugs or their
excipients/adjuvant, or to drugs of similar chemical classes.
6. Indication for or current treatment with ChEIs and/or another AD treatment
(e.g. memantine).
7. Contraindication or intolerance to MRI or PET investigations.Screening and
Treatment Epoch exclusion criteria
Participants fulfilling any of the following criteria prior to randomization
will be excluded.
Participants, who fulfill one or more exclusion criteria due to a temporary
condition, or the use of treatment requiring a specific time window prior to
randomization, can be re-screened at a later stage:
1. 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.For Cohort I (CAD 106) only, in addition,
evidence of ARIA-H as demonstrated by:
* More than four cerebral microhemorrhages (defined as diameter * 10 mm on T2*
sequence) regardless of their anatomical location
* Single area of superficial siderosis of the CNS or evidence of a prior
cerebral macrohemorrhage (> 10 mm diameter)
2. Score *yes* on item four or item five of the Suicidal Ideation Section of
the C-SSRS if this ideation occurred in the past six months, or *yes* on any
item of the Suicidal Behavior Section, except for the *Non-Suicidal
Self-Injurious Behavior* (item also included in the Suicidal Behavior Section)
if this behavior occurred in the past two years prior to screening.
3. A positive drug screen at Screening, 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 (e.g. presence of prescription drugs in urine without
evidence of prescription drug abuse), can be re-screened once.
4. Significantly abnormal laboratory results at Screening as described in
appendix 13.4 or 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
once.
5. Clinically significant active infection which has not resolved wiothin 2
weeks prior to initial dosing.
6. Current clinically significant ECG findings (e.g. sustained ventricular
tachycardia, significant second or third degree atrioventricular block without
a pacemaker, prolonged QT syndrome).
7. Use of other investigational drugs prior to screening until:
* Blood concentration has returned to Baseline (or below Serological responder
treshold) for biologics, e.g. monoclonal antibodies or antibodies induced by
active immunotherapy; or
* Within 30 days or 5 half-lives, whichever is the longest for monoclonal
antibodies or small molecules e.g. BACE-1 inhibitors.
8. Treatment in the four weeks prior to randomization with any drug or
treatment known for their potential to cause major organ system toxicity, i.e.
drugs that may require periodic safety monitoring of a specific organ or body
fluid (e.g. clozapine, tamoxifen).
9. Violations of concomitant medication restrictions as described in Table 5-3.
10. Donation or loss of 400 mL or more of blood within 8 weeks prior to
screening blood sampling and/or lumbar puncture if applicable.
11. Previous or planned Nuclear Medicine Radiology exposure that will exceed
the acceptable dosimetry exposure in the country, when adding the scheduled
study PET scans or allergy to low doses of fluorinated radioligands.
12. For Cohort II only: Participants with depigmenting or hypopigmenting
conditions or active/history of chronic urticaris in the past year.
13. For Cohort I only: Participants with previous organ transplantation or stem
cell transplantation.Exclusion criteria for participation in the biomarker CSF
sampling:
14. Contraindication to lumbar puncture, e.g. low platelet count, abnormal
prothrombin time international normalized ratio (PT-INR), history of
lumbar-spinal surgery (with the exception of microdiscectomy or laminectomy
over one level), signs or symptoms of intracranial pressure, spinal deformities
or other conditions.
Other protocol defined exclusion criteria may apply.