| 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 effects of CAD106 and CNP520 respective vs. placebo on Time-to-event, with event defined as a diagnosis of MCI due to AD or dementia due to AD, whichever occurs first during the course of the study.
- To demonstrate the effects of CAD106 and CNP520 vs. respective vs. placebo on cognition as measured by the change from Baseline to Month 60 in the APCC test score. |
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| E.2.2 | Secondary objectives of the trial |
- To demonstrate the effects of CAD106/CNP520 vs respective placebo on global clinical status as measured by the change from Baseline to Month 60 in CDR-SOB score.
- To demonstrate the safety/tolerability of CAD106/CNP520 vs respective placebo as measured by AEs, changes in MRI, lab tests, vital signs, ECG, C-SSRS, injection-related reactions from Cohort I and skinrelated AEs from Cohort II.
- To demonstrate the effects of CAD106/CNP520 vs respective placebo on cognition as measured by changes from Baseline to Month 60 on RBANS.
- To demonstrate the effects of CAD106/CNP520 vs respective placebo on function as measured by the change from Baseline to Month 60 in the ECog total scores reported by the participant and study partner, respectively.
- To demonstrate the effects of CAD106/CNP520 vs respective placebo on AD-related biomarkers as measured by change from Baseline to Months 24 and 60 in the subset of participants who consent. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Pre-screening Epoch and Genetic Disclosure Follow-up inclusion criteria:
1. 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 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.
5. Psychological 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 assessments 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, Treatment and Follow-up Epoch inclusion criteria:
Participants 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 Informed consent #2; respectively 65-75 after reaching the maximum of 20% in the younger 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.
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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| E.4 | Principal exclusion criteria |
Pre-screening Epoch and Genetic Disclosure Follow-up exclusion criteria:
1. Any disability that may prevent the participants from completing all study requirements.
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 prostrate 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.
7. Contraindication or intolerance to MRI or PET investigations.
Screening, Treatment and Follow-up Epochs 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 ARIAH as demonstrated by:
- More than four cerebral microhemorrhages regardless of their anatomical location;
- Single area of superficial siderosis of the CNS or evidence of a priorcerebral macrohemorrhage.
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" 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 or dependence. Participants with a positive drug screen not believed to be related to drug abuse or dependence, can be re-screened once.
4. Significantly abnormal laboratory results at Screening as described in Appendix 13.4 or meeting the exclusionary alert values as specified in the Lab 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 within 2weeks prior to initial dosing.
6. Current clinically significant ECG findings.
7. Use of other investigational drugs prior to screening until:
- Blood concentration has returned to Baseline (or below Serological responder threshold) for biologics, e.g. 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 aspecific organ or body fluid.
9. Violations of concomitant medication restrictions as described in Table5-3.
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 clinically relevant depigmenting or hypopigmenting conditions or active/history of chronic urticaria in the past year.
13. For cohort I only: Participants with previous organ transplantation or stem cell transplantation.
Exclusion criteria for participation in biomarker CSF sampling:
14. Contraindictaion to lumbar puncture e.g. low platelet count, abnormal PT-INR, history of lumbar-spinal surgery, signs or symptoms of intracranial pressure, spinal deformities or other conditions.
Other protocol defined exclusion criteria may apply. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Time-to-event (MCI or dementia due to AD) measured by the MCI/dementia diagnostic verification form that includes measurements of cognitive function (RBANS, MMSE), function/cognition (CDR-SOB), daily function and subjective/observer memory concerns (ECog), plus Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale, and safety MRI.
- API Preclinical Composite Cognitive (APCC) Battery derived from tests performed as part of the cognitive scales (MMSE, RBANS, and a subset of Raven’s Progressive Matrices) administered during the study. |
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| 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) |
| - Global clinical status as measured by the change in Clinical Dementia Rating Scale Sum of Boxes score. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | 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 | 4 |
| 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 | 44 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Finland |
| Germany |
| Netherlands |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| 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 | 9 |
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