| 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. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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
1. To evaluate the efficacy of BAN2401 compared to placebo by establishing the ED90 (as defined in the protocol) for BAN2401 on the Alzheimer’s Disease Composite Score (ADCOMS) at 12 months of treatment in subjects with Early Alzheimer’s Disease (EAD), defined as mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) –intermediate likelihood or mild Alzheimer’s disease dementia
2. To assess the safety and tolerability of 3 doses and 2 dose regimens of BAN2401 in subjects with EAD
Extension
1. To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD
Dosing Regimen substudy
To assess whether amyloid levels are maintained over time at less frequent dosing regimens as measured by PET SUVR
See protocol for full list of objectives. |
|
| E.2.2 | Secondary objectives of the trial |
Core
1. To evaluate the effects of BAN2401 compared to placebo on brain amyloid pathophysiology at 18 months of treatment in subjects with EAD as measured by amyloid PET
2. To evaluate the efficacy of BAN2401 compared to placebo on the ADCOMS at 18 months of treatment in subjects with EAD
3. To evaluate the efficacy of BAN2401 compared to placebo on the CDR-SB at 18 months of treatment in subjects with EAD
4. To evaluate the efficacy of BAN2401 compared to placebo on ADAS-cog in subjects with EAD at 18 months
5. To evaluate the effects of BAN2401 compared to placebo at 18 months on clinical status separately within subjects with MCI and mild AD dementia for the following assessments: ADCOMS, CDR-SB, and ADAS-cog
Extension
1. To assess if the treatment benefit in brain amyloid levels (as measured by amyloid PET) at the end of the Core Study will be maintained over time in the Extension Phase in subjects with EAD.
See protocol for full details. |
|
| 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 |
Open-Label Extension (OLE) Phase
All subjects who are ongoing in the OLE and who have completed at least 18 months of treatment in the OLE may take part in an optional dosing regimen substudy to evaluate effects on safety, PK exposure, biomarker and clinical efficacy of alternative dosing regimens for maintenance dosing of BAN2401 |
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| E.3 | Principal inclusion criteria |
Core
1.Meet NIA-AA core clinical criteria for MCI due to Alzheimer’s disease – intermediate likelihood
2.Subjects who have CDR score of 0.5 and Memory Box score of 0.5 or greater at Screening and Baseline
3.Subjects who report history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; MUST be corroborated by an informant
4.Meet the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia
5.Subjects who have CDR score of 0.5 to 1.0 and Memory Box score of 0.5 or greater at Screening and Baseline
Key Inclusion Criteria that must be met by ALL Subjects:
6.Subjects with objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the WMS-IV LMII, as follows:
a)≤15 for age 50 to 64 years
b)≤12 for age 65 to 69 years
c)≤11 for age 70 to 74 years
d)≤9 for age 75 to 79 years
e)≤7 for age 80 to 90 years
7.Positive amyloid load as indicated by 1 of the following:
a.PET assessment
b.CSF assessment of Aβ(1-42)
8.Male or female subjects aged between 50 and 90 years, inclusive
9.MMSE score equal to or greater than 22, and equal to or less than 30 at Screening and Baseline, except for the following countries, where MMSE score must be equal to or greater than 22 and equal to or less than 28 at Screening and Baseline: UK, ES, DE, SE, FR, and the NL
10.Body Mass Index >17 and <35 at Screening
11.Females must not be lactating or pregnant at Screening or Baseline All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically
12.Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception throughout the entire study period and for 35 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 35 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 35 days after study drug discontinuation.
13.Subjects who are receiving an 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 permitted concomitant medications for at least 4 weeks prior to Baseline. Use of memantine will not be allowed for Japanese subjects.
14.Must have an identified caregiver/informant The caregiver/informant 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 caregiver/informant can reliably fulfill the study requirements. A permanent caregiver/informant need not be living in the same residence with the subject. For such a caregiver/informant not residing with the subject, the investigator has to be satisfied that the subject can contact the caregiver/informant readily during the times when the caregiver/informant 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. Caregivers/informants need only to be present at visits where clinical assessment of CDR and FAQ takes place.
15.Provide written informed consent. If a subject lacks capacity to consent in the investigator's opinion, subject's assent should be obtained, if required in accordance with local laws, regulations and customs, plus written informed consent of a legal representative should be obtained
Extension
1. Have completed Visit 42 (Week 79) of the Core Study or who discontinued study drug during the Core Study due to any of the following reasons:
a. ARIA-E
b. ARIA-H (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage)
c. Prohibited or restricted medications that were prohibited during Core Study conduct but are no longer prohibited in the Extension Phase
d. Subjects who were APOE4 positive and receiving treatment with BAN2401 10 mg/kg biweekly
e. Any reason for discontinuation not related to prohibited medications, including any AE that was considered not related to study drug, and that was not severe or life-threatening.
See protocol for complete criteria |
|
| E.4 | Principal exclusion criteria |
Core
1. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the subject’s AD
2. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening
3. Any psychiatric diagnosis or symptoms, that could interfere with study procedures
4. GDS score ≥8 at Screening
5. Contraindications to MRI scanning, including cardiac pacemaker/ defibrillator, ferromagnetic metal implants
6. Evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on MRI at Screening.
7. Other significant pathological findings on brain MRI at Screening, including but not limited to: more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a single macrohemorrhage greater than 10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white matter disease; space occupying lesions; or brain tumors [ (however, lesions diagnosed as meningiomas or arachnoid cysts and < 1cm at their greatest diameter need not be exclusionary]
8. Hypersensitivity to BAN2401 or any of the excipients, or to any monoclonal antibody treatment
9. Any immunological disease which is not adequately controlled, or which requires treatment with biologic drugs during the study
10. Subjects with a bleeding disorder not under adequate control
11. Subjects who have thyroid stimulating hormone 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.
12. Abnormally low serum Vitamin B12 levels.
13. A prolonged QT/QTc interval (QTc >450 ms) as demonstrated by a repeated electrocardiogram
14. Known to be HIV positive
15. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests or ECG at Screening or Baseline which in the opinion of the principal investigator (PI), require further investigation or treatment or which may interfere with study procedures or safety
16. Uncontrolled Type 1 or Type 2 diabetes mellitus
17. Uncontrolled hypertension with a history of blood pressure consistently above 165/100 mm Hg at Screening
18. History of uncontrolled cardiovascular disease within 6 months of Screening
19. Subjects with malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male subjects). Subjects who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening need not be excluded.
20. Has a “yes” answer to Columbia Suicide Severity Rating Scale 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
21. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening.
22. Any other medical conditions which are not stably controlled, or which in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments
23. Subjects who are taking prohibited medications
24. 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
25. Participation 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
Extension
1. Subjects who discontinued from the study drug or from the Core Study for reasons other than the following:
a. ARIA-E
b. ARIA-H (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage)
c. Prohibited or restricted medications that were prohibited during Core Study conduct but are no longer prohibited in the extension phase
d. Subjects who were APOE4 positive and receiving treatment with BAN2401 10 mg/kg biweekly
e. AE that was considered not related to study drug and that was not severe or life-threatening.
See protocol for complete criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Core
1. Change from baseline in the ADCOMS
Extension
1. Safety assessments will be based on medical review of AE reports and the results of vital sign measurements, ECG, physical examinations, clinical laboratory tests, anti drug antibody (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.
Dosing Regimen substudy
1. Change from substudy baseline in brain amyloids levels as measured by amyloid PET
See protocol for complete list of endpoints. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Core Key Secondary Endpoints
1. Change from baseline at 18 months in brain amyloid pathophysiology as measured by amyloid PET
2. Change from baseline in the ADCOMS at 18 months
3. Change from baseline in CDR-SB at 18 months
4. Change from baseline in ADAS-cog at 18 months
5. Change from baseline in CSF biomarkers (Aβ[1-42], t-tau, and p-tau) at 18 months
6. Change from baseline in total hippocampal volume at 18 months using vMRI
Secondary Endpoints:
1. Change from baseline at 12 months in brain amyloid pathophysiology as measured by amyloid PET
2. Change from baseline at 12 months on clinical status for the following assessments: ADCOMS, CDR-SB, and ADAS-cog
3. Change from baseline in CSF biomarkers (Aβ[1-42], t-tau, and p-tau) at 12 months
4. Change from baseline in total hippocampal at 6 and 12 months, and in left and right hippocampus, whole brain, and total ventricular volume as measured by vMRI at 6, 12, and 18 months
Exploratory Endpoints:
1. Change from baseline in clinical status at time points not analyzed in Key Secondary and Secondary sections for each of the following: ADCOMS, ADAS-cog, CDR SB, MMSE, and FAQ
Extension
1. Change from baselines in brain amyloid levels as measured by amyloid PET at 3 months (Visit 50 [Extension Week 13], Cohort 1) or 6 months (Visit 57 [Extension Week 27], Cohort 2), and 12 and 24 months in the Extension Phase (Visit 70 [Extension Week 53], Visit 96 [Extension Week 105]) .
2. Change from end of Core Study in brain amyloid levels as measured by amyloid PET at the baseline of Extension Phase.
3. Proportion of amyloid positive subjects over time
Exploratory Endpoints
1. Change from baselines in ADCOMS, CDR-SB, ADAS-Cog, and MMSE at each visit assessed .
2. Time to worsening of CDR global scores, eg, the worsening of global CDR score is defined as an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits at which global CDR is measured.
3. Change from baselines in total hippocampal volume and other biomarkers at 12, and 24 months in the Extension Phase (Visit 70 [Extension Week 53], Visit 96 [Extension Week 105]).
See protocol for complete list of endpoints.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The ADCOMS at 18 months, vMRI at 6, 12, and 18 months. Amyloid PET at 12 and 18 months. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
- Tolerability and Immunogenicity.
- Open label extension
|
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Bayesian Adaptive Randomization |
|
| 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 | 6 |
| 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 | 31 |
| 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 |
| Japan |
| Korea, Republic of |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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