DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL- TO-MILD ALZHEIMER’S DISEASE

Inclusion criteria: • Must meet all of the following clinical criteria for MCI due to AD or mild AD 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 between 22 and 30 (inclusive) • Must have confirmed amyloid pathology consistent with AD (by PET scan or CSF measurement) • Must consent 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 150 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 600 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. Alzheimer’s Disease MedDRA version: 19.0 Level: LLT Classification code 10001896 Term: Alzheimer's disease System Organ Class: 100000004852 ;Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] Product Name: crenezumab Product Code: Ro 549‐0245/F05 Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: crenezumab CAS Number: 1095207‐05‐8 Current Sponsor code: RO5490245 Other descriptive name: Crenezumab, Anti Abeta, MABT5102A Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 180‐ Pharmaceutical form of the placebo: Concentrate for solution for infusion Route of administration of the placebo: Intravenous use Main Objective: Efficacy:evaluate crenezumab 60 mg/kg compared with placebo when admin. by IV infusion q4w over 100 wks as measured(final outcome assessment at Wk 105,4 wks after the final dose)Change from baseline on CDR‐sum of boxes Safety:evaluate the safety of crenezumab compared with placebo in patients with prodromal to mild AD on the basis of the follow. 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,Non‐serious adverse events of special interest, specific. pneumonia •Adverse events,as assessed by magnetic resonance imaging:amyloid related imaging abnormalities edema/effusion,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 ;Secondary Objective: Efficacy: secondary efficacy objective for this study is to evaluate the benefits of crenezumab versus placebo administered to patients by IV infusion over 100 weeks through assessment of the following endpoints •Cognition, as measured by the ADAS‐Cog (subscale) 13 (ADAS Cog 13) •Effect on severity of dementia, assessed using the CDR‐Global Score (CDR GS) •Effect on cognition, assessed using the MMSE, ADAS‐COG12 •Effect on function, assessed using the ADCS‐ADL instrumental subscale (ADCS iADL) and ADCS‐ADL total score •Effect on behavioral and neuropsychological symptoms of AD, assessed using the Neuropsychiatric Inventory Questionnaire (NPI‐Q •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 ;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 ;Timepoint(s) of evaluation of this end point: Change from baseline at week 105 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 measured by the ADAS‐Cog (subscale) 13 (ADAS Cog 13) ;Timepoint(s) of evaluation of this end point: Change from baseline at week 105