| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mild cognitive impairment or mild dementia caused by Alzheimer's disease which results in progressive memory loss, reasoning, language and other mental abilities. |
|
| 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 | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10074616 |
| E.1.2 | Term | Prodromal Alzheimer's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
Core
• To evaluate the efficacy of BAN2401 in subjects with early Alzheimer’s disease (EAD) by determining the superiority of BAN2401 compared with placebo on the change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months of treatment.
Extension
• To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD in the Extension Phase.
• To evaluate whether the long-term effects of BAN2401 as measured by the CDR-SB at the end of the Core Study is maintained over time in the Extension Phase |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objective
- To determine whether BAN2401 is superior to placebo in reducing brain amyloid levels as measured by amyloid positron emission tomography (PET) using Centiloids at 18 months
- To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the AD Assessment Scale–Cognitive Subscale14 (ADAS-cog14) at 18 months of treatment
- To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the AD composite score (ADCOMS) at 18 months
of treatment
- To evaluate the efficacy of BAN2401 in subjects with EAD by determining the superiority of BAN2401 compared with placebo on the change from baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL) at 18 months of treatment
For all other objectives see protocol. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Longitudinal amyloid PET assessments will be conducted at 3, 6, 12, and 18 months of treatment in consenting subjects from participating countries to demonstrate target engagement and to assess amyloid clearance for BAN2401. Longitudinal CSF assessments will be performed at 12 and 18 months of treatment for soluble biomarker analysis (eg, Aβ[1-42], Aβ[1-40], neurogranin [CSF only], NFL, t-tau, and p-tau) in consenting subjects in participating countries to assess effects on indicators of disease pathology. (revised per Amendment 01).
Longitudinal tau PET assessments will be performed at 13 and 18
months of treatment using a the sponsor-supplied tau PET imaging
agent. For subjects who discontinue early from the study drug, an early termination amyloid PET scan will be performed only if the preceding amyloid PET assessment was performed 3 or more months prior to the early termination visit. The medical monitor must be consulted before an early termination tau PET scan is performed. (revised per
Amendment 01)
An optional SC substudy to the OLE will be available in the US and JP only.
An optional AI SC substudy to the OLE will be available.
See protocol for full details. |
|
| E.3 | Principal inclusion criteria |
Diagnosis
MCI due to AD–intermediate likelihood:
1. Meet the NIA-AA core clinical criteria for MCI due to AD–intermediate likelihood.
2. Have a global CDR score of 0.5 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
3. Report a history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; must be corroborated by an informant.
Mild AD dementia:
4. Meet the NIA-AA core clinical criteria for probable AD dementia.
5. Have a global CDR score of 0.5 to 1.0 and a CDR Memory Box score of 0.5 or greater at Screening and Baseline.
Key Inclusion Criteria that must be met by all subjects:
6. Objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the Wechsler Memory Scale IV-Logical Memory :
a. ≤15 for age 50-64 years
b. ≤12 for age 65-69 yrs
c. ≤11 for age 70-74 yrs
d. ≤9 for age 75-79 yrs
e. ≤7 for age 80-90 yrs
7. Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following:
a. PET assessment of imaging agent uptake into brain. Note: amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for lumbar puncture (LP) to obtain CSF for testing of eligibility.
b. CSF assessment of t-tau/Aβ[1-42]
NOTE1: Subjects who are on anticoagulant therapy may not participate in CSF assessments.
NOTE2: Subjects may consent to both the PET and CSF assessments, but to confirm eligibility, a positive amyloid result is needed in only 1 of the 2 procedures (ie, the subject will be eligible even if 1 of the 2 results does not meet its eligibility criterion).
Subjects who consent to amyloid PET or CSF at Screening for the purposes of eligibility are not required to participate in the amyloid PET, tau PET, or CSF longitudinal substudies. Use of a historical amyloid positive PET (conducted within 12 months before the planned date of randomization) is acceptable for determination of eligibility provided the subject did not participate in any clinical studies involving anti-amyloid therapies subsequent to the PET assessment. Historical PET will not suffice for the baseline assessment if the subject wishes to consent to the amyloid PET longitudinal substudy. The historical imaging data must be made available to the sponsor to confirm amyloid positivity.
8. Male or female subjects aged ≥50, ≤90 years, at the time of informed consent.
9. MMSE score greater than or equal to 22 at Screening and Baseline and less than or equal to 30 at Screening and Baseline.
10. BMI >17 and <35 at Screening.
11. If receiving an approved AD treatment, such as AChEIs, or memantine, or both for AD, must be on a stable dose for at least 12 weeks prior to Baseline. Treatment-naïve subjects for AD can be entered into the study. Unless otherwise stated, subjects must have been on stable doses of all other (ie, non-AD-related) permitted concomitant medications for at least 4 weeks prior to Baseline. Use of memantine will not be allowed for Japanese subjects.
12. Have an identified study partner (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The study partner must provide separate written informed consent. In addition, this person must be willing and able to provide follow-up information on the subject throughout the course of the study. This person must, in the opinion of the investigator, spend sufficient time with the subject on a regular basis such that the study partner can reliably fulfill the study requirements. A permanent study partner need not be living in the same residence with the subject. For such a study partner not residing with the subject, the investigator has to be satisfied that the subject can contact the study partner readily during the times when the study partner is not with the subject. If in doubt about whether a subject's care arrangements are suitable for inclusion, the investigator should discuss this with the medical monitor. Study partners need to participate in person for visits where clinical assessment of CDR (global and CDR-SB), EQ-5D-5L, QOL-AD, ADCS MCI-ADL and Zarit Burden Interview take place.
13. Provide written informed consent. If a subject lacks capacity to
consent in the investigator's opinion, the subject's assent should be
obtained, if required in accordance with local laws, regulations and
customs, plus the written informed consent of a legal representative
should be obtained (capacity to consent and definition of legal
representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to
participate in this study (eg Germany and Spain), they will not be
enrolled.
13. See protocol for full details. |
|
| E.4 | Principal exclusion criteria |
1. Females who are breastfeeding or pregnant at Screening or Baseline
2. Females of childbearing potential who:
a. Within 28 days before study entry, did not use a highly effective method of contraception
b. Do not agree to use a highly effective method of contraception throughout the entire study period and for 28 days after study drug discontinuation.
3. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the subject’s AD.
4. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening.
5. Any psychiatric diagnosis or symptoms that could interfere with study procedures in the subject.
6. GDS score greater than or equal to 8 at Screening.
7. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants.
8. Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD.
9. Other significant pathological findings on brain MRI at Screening - see protocol for further details.
10. Hypersensitivity to BAN2401 or any of the excipients, or to any monoclonal antibody treatment.
11. Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic
immunosuppressants, or plasmapheresis during the study.
12. Subjects with a bleeding disorder that is not under adequate control (including a platelet count <50,000 or INR >1.5 for subjects who are not on anticoagulant treatment. Subjects who are on anticoagulant therapy should have their anticoagulant status optimized and be on a stable dose for 4 weeks before Screening.
Subjects who are on anticoagulant therapy are not permitted to participate in CSF assessments.
13. Have thyroid stimulating hormone (TSH) above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator. This applies to all subjects whether or not they are taking thyroid supplements.
14. Abnormally low serum vitamin B12 levels for the testing laboratory
15. Known to be HIV positive.
16. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which in the opinion of the PI require further investigation
17. Subjects with malignant neoplasms within 3 years of Screening (see protocol for exceptions).
18. Answer “yes” to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.
19. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. Subjects who test positive for benzodiazepines or opioids in urine drug testing need not be excluded if in the clinical opinion of the investigator, this is due to the subject taking prior/concomitant medications containing benzodiazepines or opioids for a medical condition and not due to drug abuse.
20. Any other medical conditions which are not stably and adequately controlled, or which in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments.
21. Subjects who are taking prohibited medications.
22. Participation in a clinical study involving any therapeutic monoclonal antibody, protein derived from a monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months before Screening (anti-amyloid therapies within 1 year before screening), unless it can be documented that the subject was randomized to placebo.
23. Participation in a clinical study involving any anti-amyloid therapies (including any monoclonal antibody therapies and any BACE inhibitor therapies) unless it can be documented that the subject only received placebo.
24. Subjects who have any known prior exposure to BAN2401.
25. Subjects who were dosed in a clinical study involving any new chemical entities for AD within 6 months prior to Screening unless it can be documented that the subject was in a placebo treatment arm.
26. Participated in any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the subject was in a placebo treatment arm.
27. Planned surgery which requires general anesthesia that would take place during the study.
28. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately.
See protocol for full list.
Extension:
See protocol for full details |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Core
• Change from baseline in the CDR-SB at 18 months .
Extension
• Safety assessments will be based on medical review of AE reports and the results of vital sign measurements, ECG, physical examinations, clinical laboratory tests, ADA test results, and any relevant test of cognitive function to evaluate decline. Additionally, MRI assessments of microhemorrhage, vasogenic edema, and other clinically significant abnormalities will be evaluated.
• Change from core study baseline in CDR-SB |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints for this study are:
- Change from baseline in amyloid PET using Centiloids at 18 months for brain amyloid levels
- Change from baseline in ADAS-cog14 at 18 months
- Change from baseline in ADCOMS at 18 months
- Change from baseline in ADCS MCI-ADL at 18 months
OTHER SECONDARY ENDPOINTS
Refer to protocol
BM Endpoints
Refer to protocol |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | No |
| 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 | 2 |
| 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 | 4 |
| 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 |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Sweden |
|
| 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
|
| Last patient, last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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