| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Alzheimer's disease is a progressive neurologic disorder that causes brain cells to die and leads to memory and thinking problems. |
|
| 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 | HLT |
| E.1.2 | Classification code | 10001897 |
| E.1.2 | Term | Alzheimer's disease (incl subtypes) |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 evaluate the efficacy of gantenerumab compared with control on cognition |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate the efficacy of gantenerumab compared with control on clinical progression based on time from randomization to clinical progression to mild cognitive impairment (MCI) or dementia and time to onset of confirmed clinical progression
● To evaluate the efficacy of gantenerumab compared with control on cognition and/or function
● To evaluate the safety of gantenerumab compared with placebo
● To evaluate biomarkers of pharmacodynamics of gantenerumab compared with control |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Main Study
● Participants who:
- Are age 60-80 years (inclusive) at the time of signing the ICF
- Cognitively unimpaired with a screening Clinical Dementia Rating Global Score (CDR-GS) of 0, and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Memory Index (DMI) >=80
- Show evidence of cerebral amyloid accumulation
- Have an available person (referred to as a “study partner” throughout the protocol) who: a) Has frequent and sufficient contact with the participant, and is willing and able to provide accurate information regarding the participant’s cognitive and functional abilities, signs the necessary ICF(s), and has sufficient cognitive capacity to accurately report on the participant’s cognitive and functional abilities; b) Is in sufficiently good general health to have a high likelihood of maintaining the same level of interaction with the participant and participation in study procedures throughout the duration of the study; c) Is fluent in the language of the tests used at the study site; d) Every effort should be made to have same study partner participate throughout the duration of the study
- Are fluent in the language of the tests used at the study site
- Have adequate visual and auditory acuity, sufficient to perform neuropsychological testing
- Have agreed not to donate blood or blood products for transfusion for the duration of the study and for 1 year after the final dose of study drug
- Have agreed not to participate in other interventional research studies for the duration of this trial
● For women of childbearing potential:
- Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods during the treatment period and for at least 17 weeks after the final dose of study Treatment
Optional Blood-Based Biomarker Prescreening Procedure
● Participants who:
- Are age 60-80 years (inclusive) at the time of signing the Blood-Based Biomarker Prescreening Informed Consent Form (ICF)
- Do not have a known clinical diagnosis of cognitive impairment, MCI, prodromal AD, or any form of dementia |
|
| E.4 | Principal exclusion criteria |
Exclusions Related to central nervous system (CNS) Disorders
Participants who:
- Show any evidence of an underlying neurological or neurodegenerative condition that may lead to cognitive impairment other than AD
- Have a clinical diagnosis of MCI, prodromal AD, or any form of dementia
- Have a history or presence of intracranial or intracerebral vascular malformations, aneurysm, subarachnoid hemorrhage, intracerebral macrohemorrhage, or posterior reversible encephalopathy syndrome
- Have a history of ischemic stroke with clinical symptoms or an acute event that is consistent with a transient ischemic attack or severe, clinically significant CNS trauma
- Have a history or presence of intracranial mass lesion that could potentially impair cognition or lead to progressive neurological deficits
- Have infections that may affect brain function or a history of infections that resulted in neurologic sequelae
- Have a history of major depression, schizophrenia, schizoaffective disorder, or bipolar disorder
- Are at risk for suicide
- Have had history of alcohol and/or substance abuse or dependence
Exclusions Related to Imaging Findings
Participants who:
- According to the MRI central reader, show MRI evidence of any of the following:
* >1 lacunar infarcts
* Any territorial infarct >1 cm3
* Any white matter lesion that corresponds to an Overall
Fazekas score of 3
- Have a combined number of microbleeds and areas of leptomeningeal hemosiderosis on the MRI of >5
- Have a presence of any other significant cerebral abnormalities
- Are not able to tolerate MRI procedures or have a contraindication to MRI
Exclusions Related to Cardiovascular Disease
Participants who:
- Have a history or presence of clinically significant systemic vascular disease or atrial fibrillation
- Experienced unstable or clinically significant cardiovascular disease
- Have a history or presence of heart failure
- Have had uncontrolled hypertension
Exclusions Related to Hepatic and Renal Disorders
Participants who:
- Have chronic kidney disease or confirmed and unexplained impaired hepatic function
Exclusions Related to Infections and Immune Disorders
Participants who:
- Have a history of, or are known to currently have an HIV infection, or hepatitis B or hepatitis C virus infection or spirochete infection of the CNS
- Have a history or presence of systemic autoimmune disorders
- Have systemic immunosuppression or immunomodulation
- Have current COVID-19 infection
Exclusions Related to Metabolic and Endocrine Disorders
Participants who:
- Have abnormal thyroid function
- Show evidence of folic acid deficiency or vitamin B-12 deficiency
- Have a screening hemoglobin A1c (HbA1c) >8% or poorly controlled insulin-dependent diabetes with hypoglycemic episodes
Exclusions Related to Medications
● Any previous administration of:
- Gantenerumab
- Active immunotherapy (vaccine) that is being evaluated to prevent or postpone cognitive decline
- Passive immunotherapy (Ig) or other long-acting biologic agent to prevent or postpone cognitive decline
● Any other investigational treatment within 5 half-lives or 6 months
● Any previous administration of sodium oligomannate (GV-971)
● Any previous treatment with medications specifically intended to treat symptoms related to Parkinson’s disease or any other neurodegenerative disorder
● Anticonvulsant medications, typical and atypical anti-psychotic or neuroleptic medications, anticoagulation medications
● Psychedelic drugs and substances, recreational cannabis and illicit use of opioids or ketamine
● Medical marijuana, chronic use of prescribed opiates or opioids for pain management and chronic use of prescribed benzodiazepines, barbiturates and hypnotic medications, medical food supplements are allowed if on a stable dose for at least 1 month prior to screening
● Nootropics and stimulant medications
● Any previous treatment with cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists
Additional Exclusions
● Participants who:
- Are pregnant or breastfeeding, or intending to become pregnant
- Have a deformity of the lumbosacral region of the spine, clinically significant abnormal screening blood, CSF or urine results, impaired coagulation, history of cancer, severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins, hypersensitivity to any gantenerumab excipients
- Have any other severe or unstable medical conditions that could be expected to progress, recur, or change to such an extent that it could put the participant at special risk, interfere with the participant’s ability to complete the study assessments, or would require the equivalent of institutional or hospital care
- Reside in a skilled nursing facility such as a convalescent home or long-term care facility
● Planned or recent exposure to ionizing radiation that exceeds recommended local guidelines |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Change from baseline to Year 4 in the Preclinical Alzheimer’s Cognitive Composite-5 (PACC-5) score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Time from randomization to clinical progression to MCI or dementia due to AD based on the diagnosis of the independent Clinical Adjudication Committee (iCAC)
2. Time to onset of confirmed clinical progression, defined as the time from randomization to the first occurrence of two consecutive visits (approximately 6 months apart) with a CDR-GS >0
3. Change from baseline to Year 4 in the Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version (A-IADL-Q-SV) and the Cognitive Function Instrument acute (CFIa)
4. Change from baseline to Year 4 in the Clinical Dementia Rating Sum of Boxes (CDR-SB)
5. Nature, frequency, severity, and timing of adverse events, serious adverse events, and adverse events of special interest
6. Physical examinations (including neurological systems), vital signs, blood tests, electrocardiograms (ECGs), and Columbia-Suicide Severity Rating Scale (C-SSRS)
7. Nature, frequency, severity, and timing of MRI findings: amyloid-related imaging abnormality-edema/effusion (ARIA-E) and amyloid-related imaging abnormality-hemosiderin deposition (ARIA-H)
8. Nature, frequency, severity, and timing of injection-site reactions (ISRs)
9. Presence of anti-drug antibodies (ADAs) during the study relative to the presence of ADAs at baseline
10. Change in brain amyloid load over time, as measured by amyloid positron emission tomography (PET) in a subset of participants
11. Change in brain tau load over time, as measured by tau PET in a subset of participants
12. Change in cerebrospinal fluid (CSF) biomarkers, including, but not limited to, Aβ1-42, Aβ1-40, NfL, pTau, and tTau in a subset of participants
13. Change in blood-based biomarkers biomarkers, including, but not limited to, Aβ1-42, Aβ1-40, NfL, pTau, and tTau in a subset of participants
14. Change in magnetic resonance imaging (MRI)-derived measurements over time, including, but not limited to, volumetric changes in whole-brain, ventricles, hippocampus, or other structures in all participants |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. Baseline to Year 4 (Week 211)
5-9. Baseline to Week 227 (or 15 weeks after Early Term Visit) (Note: The primary comparison for safety will be between active gantenerumab and placebo)
10-14. For CSF and PET: Baseline to week 211/For MRI: Baseline to Week 227 (or 15 weeks after Early Term Visit)
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Control arm: pts randomized to pcb + pts randomised to pcb and starting active tx (ref protocol 4.1 |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 | 60 |
| 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 |
| Japan |
| Korea, Republic of |
| New Zealand |
| United States |
| France |
| Poland |
| Sweden |
| Netherlands |
| Spain |
| Germany |
| Italy |
| Belgium |
| Ireland |
| Russian Federation |
| United Kingdom |
|
| 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
|
| A participant is considered to have completed the study if he or she has completed all phases of the study, including the safety FU visit shown in the schedule of activities (see Section 1.3). The end of this study is defined as the date of the LPLV in the study or the date at which the last data point required for safety analyses or safety FU is received from the last participant, whichever occurs later. The end of the study is expected to occur 227 weeks after the last participant randomized. |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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