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 | HLT |
E.1.2 | Classification code | 10001897 |
E.1.2 | Term | Alzheimer's disease (incl subtypes) |
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 |
Double-blind treatment period (Part 1):
To evaluate the efficacy of gantenerumab administered to patients by SC injection over 100 weeks vs. placebo on measures of cognition (ADAS-Cog) and function (ADCS-ADL). Based on recent findings from the SCarlet RoAD study and from other studies on anti-amyloid antibodies, the study has been amended to allow for higher doses of gantenerumab to be examined in an open-label extension
Open-label extension (Part 2):
To evaluate the safety and tolerability of gantenerumab at higher doses (up to 1200 mg) focusing on physical and neurologic examinations, vital signs, blood safety tests, ECG, and AE monitoring |
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E.2.2 | Secondary objectives of the trial |
Part 1:
1. To evaluate the benefits of gantenerumab vs placebo administered to patients by SC injection over 100 weeks on slowing clinical decline and disease progression by assessing the following:
• Time to clinically evident decline
• Change from baseline at Week 104 in CDR-SB
• ADAS-Cog responder
• Disease pathology biomarkers
2. Additional secondary endpoints
· Global: Effect on severity of dementia and global measures of cognition and function
· Cognition: Effect on cognition
· Behavior: Effect on behavioral and neuropsychological symptoms of AD
· Other AD symptoms and effects: Effect of gantenerumab on health related QoL, patient-individualized goal achievement, on caregiver emotional well-being, on the amount of assistance patients with dementia require in performing daily activities
Part 2:
To evaluate the effect of higher doses of gantenerumab on imaging biomarkers, CSF biomarkers, and clinical outcome measures, and to explore the PK at the higher doses
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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 |
WN28745-PET Substudy, version 2, dated 03/12/2015.
Protocol title: PET IMAGING SUBSTUDY ASSOCIATED WITH: A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER, EFFICACY, AND SAFETY STUDY OF GANTENERUMAB IN PATIENTS WITH MILD ALZHEIMER’S DISEASE; PART II: OPEN-LABEL EXTENSION FOR PARTICIPATING PATIENTS
The primary objective of the WN28745-PET substudy is to assess changes in amyloid load over time using florbetapir in patients enrolled in Study WN28745 who are treated with gantenerumab. This patient population has probable mild AD (based on NINCDS/ADRDA criteria) or probable major NCD due to AD of mild severity (based on the DSM-5 criteria)
The secondary objective of the WN28745-PET substudy is to assess the concordance between positivity or negativity on CSF Aβ1−42 testing and amyloid PET visual read at WN28745 Part 1 study entry.
WN28745-Cardiac PET Substudy, version 2, dated 03/12/2015
Protocol title: CARDIAC PET IMAGING SUBSTUDY ASSOCIATED WITH: A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER, EFFICACY AND SAFETY STUDY OF GANTENERUMAB IN PATIENTS WITH MILD ALZHEIMER’S DISEASE; PART II: OPEN-LABEL EXTENSION FOR PARTICIPATING PATIENTS
Objectives: The primary objective of the cardiac PET substudy is to assess changes in amyloid load in heart over time using florbetapir F18 in patients enrolled in the Study WN28745 and the brain only PET substudy who are treated with gantenerumab. This patient population has probable mild AD (based on NINCDS/ADRDA criteria) or probable major NCD due to AD of mild severity (based on the DSM-5 criteria). |
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E.3 | Principal inclusion criteria |
Part 1
- Adult patients, 50 to 90 years of age, inclusive
- Clinical diagnosis of probable mild Alzheimer disease based on NINCDS/ADRDA criteria or major NCD due to AD of mild severity, whether or not receiving AD approved medication
- Availability of a person ('caregiver') who in the investigator's judgment has frequent and sufficient contact with the patient, and is able to provide accurate information regarding the patient's cognitive and functional abilities
- Fluency in the language of the tests used at the study site
- Willingness and ability to complete all aspects of the study
- Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
- If currently receiving approved medications for AD, doses must have been stable for 3 months prior to screening
- Agreement not to participate in other research studies for the duration of this trial and its associated substudies
Part 2
- All patients who have been randomized and are actively participating in the study at the time of the amendment approval in their respective country will be eligible to participate in the OLE. Patients in the open label extension will be given the option of extending open-label treatment beyond the initial 2 years |
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E.4 | Principal exclusion criteria |
Part 1
- Dementia or NCD due to a condition other than AD, including, but not limited to, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, Huntington disease, or vascular dementia
- History or presence of clinically evident vascular disease potentially affecting the brain that in the opinion of the investigator has the potential to affect cognitive function
- History or presence of stroke within the past 2 years or documented history of transient ischemic attack within the last 12 months
- History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease with associated cognitive deficits
- History of schizophrenia, schizoaffective disorder, or bipolar disorder
- Alcohol and/or substance use disorder (according to the DSM-5) within the past 2 years (nicotine use is allowed)
- History or presence of atrial fibrillation
- Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, cardiac failure New York Heart Association Class II or higher)
- Uncontrolled hypertension
- Chronic kidney disease
- Impaired hepatic function |
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E.5 End points |
E.5.1 | Primary end point(s) |
Double-blind treatment period (part 1):
1. Mean change in Alzheimer's Disease Activity Scale-Cognitive subscale 13 (ADAS-Cog13) scores
2. Mean change in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores
Open label extension (Part 2):
3. safety and tolerability of gantenerumab
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Double-blind treatment period (Part 1):
1-2.Up to 2 years
Open label extension (Part 2):
3.Up to approximately 4 years of open label
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E.5.2 | Secondary end point(s) |
Double-blind treatment period (Part 1)
1.Change in biomarkers (t-tau, p-tau, Abeta 1-42 levels) in cerebral spinal fluid
2. Change in MRI volumetry, assessed on structural MRI
3. Change in Clinical Dementia Rating (CDR-SB/CDR-GS)
4. Change in neuropsychiatric behaviour: Neuropsychiatric Inventory (NPI) total and domain scores
5. Change in cognition: MMSE total score
6. Safety: Incidence of adverse events, serious adverse events and treatment discontinuations
7. Change in Clinical Dementia Rating-Sum of Boxes (CDR-SB)
8. ADAS-Cog responder
Open label extension (Part 2):
9. Explore the effect of gantenerumab on clinical outcome measures and biomarker measures
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Double-blind treatment period (part 1):
1-8. From baseline to Week 104
Open-label extension (part 2):
9. at OLE week 104
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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 | 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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarkers, exploratory biomarkers, clinical genotyping, imaging. |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
Part 2 of the study is open label |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
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 |
Brazil |
Canada |
Guatemala |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Turkey |
United States |
Belgium |
Denmark |
Finland |
France |
Germany |
Hungary |
Italy |
Poland |
Portugal |
Sweden |
United Kingdom |
Bulgaria |
Netherlands |
Spain |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | No |
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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The end of the study is defined as the date when the LPLV occurs or the date on which the last datapoint required for safety follow-up is received from the last patient in the OLE. The LPLV is expected to occur 152 weeks after the last patient is enrolled in Part 2 (i.e., 52 weeks after the final dose). |
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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 | 5 |
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 | 5 |
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 |