E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prodromal Alzheimer’s Disease |
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E.1.1.1 | Medical condition in easily understood language |
Prodromal Alzheimer’s Disease |
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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 | 10066571 |
E.1.2 | Term | Progression of 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 evaluate the effect of gantenerumab doses 105 mg and 225 mg given subcutaneous (SC) every 4 weeks (Q4W) vs. placebo on the change in the Clinical Dementia Rating scale Sum of Boxes (CDR-SOB), a global measure of cognition and functional ability. Dosing was stopped after a planned futility interim analysis that indicated low probability of meeting the primary outcome measure with the doses studied. Additional analyses suggested that higher doses of gantenerumab may have clinically relevant effects on cognition and function and are being tested in the open-label extension.
Open-label extension (OLE):
• To assess the short-term and long-term safety and tolerability of gantenerumab given at doses up to 1200 mg SC Q4W by magnetic resonance imaging (MRI), physical and neurological examinations, vital signs, blood safety tests, electrocardiogram (ECG)s, Columbia-Suicide Severity Rating Scale (C-SSRS), and adverse event monitoring |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of gantenerumab vs. placebo
- On cognition, on functioning and on onset of dementia
- On the safety and tolerability of gantenerumab
- On volumetric measures of the brain and structures
- On change in cerebrospinal fluid biomarker measures (CSF)
• Pharmacotkinetics
• Antidrug antibodies (ADAs), and if relevant, evaluate its effect on the pharmacokinetic, pharmacodynamic, efficacy and safety parameters.
Open-label extension
• To evaluate the effect of 1200 mg gantenerumab SC Q4W over time compared to baseline and to start of
open-label extension
- On changes in amyloid load in the brain by PET using Florbetapir - 18F
- On volumetric measures of the brain
- On clinical outcomes (cognition and functioning)
• To explore pharmacokinetics and ADAs with higher gantenerumab 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 |
WN25203D-PET, 16 September 2015
Sub-study to protocol WN25203, using positron emission tomography (PET) with an amyloid tracer to assess changes in amyloid load over time in subjects with Prodromal Alzheimer’s Disease |
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E.3 | Principal inclusion criteria |
- Adult patients, 50-85 years of age
- Patients with prodromal Alzheimer's Disease who are not receiving memantine or cholinesterase inhibitors
- Has a study partner who is able to provide accurate information as to the patient's cognitive and functional abilities, who agrees to provide information at clinic visits which require partner input for scale completion
- Has had sufficient education or work experience to exclude mental retardation
- Study partner has noticed a recent gradual decrease in patient's memory (e.g. over the last 12 months), which the patient may or may not be aware of
- Screening MMSE score of 24 or above
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E.4 | Principal exclusion criteria |
- Other prior or current neurologic or medical disorder which may currently or during the course of the study impair cognition or psychiatric functioning
- A history of stroke
- A documented history of transient ischemic attack within the last 12 months
- History of schizophrenia, schizoaffective or bipolar disorder
- Currently meets criteria for major depression
- Within the last 2 years, unstable or clinical significant cardiovascular disease (e.g. myocardial infarction, angina pectoris)
- Abnormal brain MRI scan
Open label extension:
- Prematurely discontinued from double-blind treatment for safety reasons affecting participation in the study
- Abnormal brain MRI scan
- Received another investigational medication after the end of double-blind treatment
- Participation deemed inappropriate by investigator or Sponsor |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Change in CDR-SOB
2. Open-label extension:
To assess long-term and short-term safety and tolerability of gantenerumab (nature and incidence of adverse events; MRI findings)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Double-blind treatment period: 2 years with option for 2 additional years
2. Open-label extension: Up to 5 years after double-blind
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E.5.2 | Secondary end point(s) |
1. Change in cognition assessed with Alzheimer Disease Assessment Scale-Cognition , Mini Mental State Exam, Cambridge Neuropsychological Test Automated Battery (double-blind only), and Free and Cued Selective Reminding Test – Immediate Recall (double-blind only)
2. Change in functioning assessed with Functional Activities Questionnaire
3. Change in cerebrospinal fluid biomarker measures (T-tau, P-tau, and Abeta 1-42; double-blind only)
4. Change in brain amyloid load using PET Positron Emission Tomography
5. Pharmacokinetics: gantenerumab levels
6. Safety (nature and incidence of adverse events; MRI findings)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-6. double-blind, 2 years; open-label extension, 3 years |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarkers, Explanatory Biomarkers, Clinical Genotyping, |
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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 |
OOpen-label extension (Part 3 of the study) |
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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 | 3 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 67 |
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 |
Belgium |
Brazil |
Canada |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Poland |
Portugal |
Russian Federation |
Spain |
Sweden |
Turkey |
United Kingdom |
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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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The end of the study will be considered to be the date of the last visit (including the last scheduled follow-up visit according to study protocol) of the last patient in the study. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |