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 | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | 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 |
Efficacy:evaluate crenezumab 60 mg/kg compared with placebo when admin. by IV infusion q4w over 100 wks as measured by the CDR-SB (final outcome assessment at Wk 105,4 wks after the final dose)
Safety: evaluate the safety of crenezumab compared with placebo in patients with prodromal to mild AD on the basis of the following endpoints
•Nature,frequency,severity and timing of adverse events and serious adverse events
•Physical and neurologic examinations,vital signs, blood tests,ECGs,Columbia Suicide Severity Rating Scale
•AEs of special interest, specific. pneumonia
•Adverse events,as assessed by magnetic resonance imaging:amyloid related imaging abnormalities edema/effusion and amyloid related imaging abnormalities hemosiderin deposition
•The immunogenic potential of crenezumab through measurement of antibodies directed against crenezumab and other components of the drug product,assessment of their relationship with other outcome measures
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E.2.2 | Secondary objectives of the trial |
Efficacy: secondary efficacy objectives for this study are to evaluate the benefits of crenezumab versus placebo administered to patients by IV infusion Q4W over 100 weeks through assessment of the following endpoints
Change from baseline to Week 105 on:
•Cognition, as assessed by the ADAS-Cog (subscale) 13 (ADAS Cog 13) and 11 (ADAS-Cog-11)
• severity of dementia, assessed using the CDR-Global Score (CDR GS) and MMSE
• function, assessed using the ADCS-ADL instrumental subscale (ADCS iADL) and ADCS-ADL total score
• neuropsychological symptoms, assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) total score
•Effect of crenezumab on health−related quality of life (QoL), assessed using the Quality of Life−Alzheimer’s Disease scale, caregiver burden, assessed using the Zarit Caregiver Interview for Alzheimer’s Disease scale and on health outcomes in patient and caregiver as measured by EQ-5D
• Measure of dependence derived from the ADCS-ADL score
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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 |
ECG SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
CONCORDANCE SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
PET LONGITUDINAL SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
CSF LONGITUDINAL SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
RESEARCH SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE |
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E.3 | Principal inclusion criteria |
• Must meet clinical criteria for MCI due to AD or mild AD (per NIAAA criteria) and must have:
• A Clinical Dementia Rating (CDR)-Global Score of 0.5 or 1.0
• Objective evidence of cognitive impairment at screening
• An MMSE score ≥22
• Must have evidence of AD pathology confirmed by positive amyloid
assessment (by PET scan or CSF measurement)
• Must consent to genotyping for apolipoprotein E (ApoE)
• If using drugs to treat symptoms related to AD, doses must be stable for at least 3 months prior to screening
• Must have a reliable study partner or caregiver
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E.4 | Principal exclusion criteria |
• Any medical or neurological condition (other than Alzheimer's Disease) that might result in cognitive impairment.
• Have had a stroke resulting in clinical symptoms within 2 years or Transient Ischemic Attack (TIA) within 6 months
• History of serious psychiatric illness or untreated major depressive disorder
• History of unstable angina, myocardial infarction, advanced chronic heart failure within 2 years prior to screening
• Have human immunodeficiency virus (HIV) infection
• Relevant brain hemorrhage or cerebrovascular abnormalities
• Any contraindications to brain magnetic resonance imaging (MRI) scans
• Alcohol or substance abuse in past 2 years
• Anti-coagulation medications within 3 months of screening – antiplatelet therapies including clopidogrel are permitted.
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate crenezumab 60 mg/kg compared with placebo when administered by IV infusion q4w over 100 weeks as measured by the following primary endpoint (final outcome assessment at Week 105, 4 weeks after the final dose): Global outcomes, as assessed by the CDR SB
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline at week 105 |
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E.5.2 | Secondary end point(s) |
To evaluate the benefits of crenezumab versus placebo administered to patients by IV infusion q4w over 100 weeks through assessment of the following endpoints: Effect on cognition, as assessed by the ADAS-Cog (subscale) 13 (ADAS Cog 13) and 11 (ADAS-Cog-11); effect on dementia severity as assessed by CDR Global Score (CDR-GS) and MMSE; effect on function as assessed by the ADCS-ADL total score and the ADCS-instrumental ADL subscore; effect on a measure of dependence derived from the ADCS-ADL score; effect on neuropsychological symptoms
assessed by Neuropsychiatric Inventory Questionnaire (NPI-Q)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change from baseline at week 105 |
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
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 | No |
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 |
PET Ligand (florbetapir F18) |
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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 | 119 |
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 |
Australia |
Austria |
Belgium |
Bulgaria |
Canada |
Costa Rica |
Croatia |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Hong Kong |
Hungary |
Italy |
Japan |
Korea, Republic of |
Lithuania |
Mexico |
Poland |
Portugal |
Russian Federation |
Slovenia |
Spain |
Sweden |
Switzerland |
Turkey |
Ukraine |
United Kingdom |
United States |
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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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last patient, last visit (LPLV) occurs or the date at which the last data point required for safety analyses or safety follow up is received for the last patient, whichever occurs later. LPLV for the double blind treatment period is expected to occur 153 weeks after the last patient is enrolled (i.e., 52 weeks after the last dosing visit at week 101) |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |