CREAD 2: A Study of Crenezumab Versus Placebo to Evaluate the Efficacy and Safety in Participants With Prodromal to Mild Alzheimer's Disease (AD)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03114657
• Collaborator: (none)
• Enrollment: 806
• Locations: 211
• Arms: 2
• Actual Duration (Months): 26.4
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The primary efficacy assessment will be performed at 105 weeks. The participants who do not enter open-label extension will enter for a long term follow-up period for up to 52 weeks after the last crenezumab dose (Week 153).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Crenezumab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 806 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 29, 2017
• Actual Primary Completion Date: Jun 11, 2019
• Actual Study Completion Date: Jun 11, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Drug: Placebo; Placebo was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.
Experimental: Crenezumab Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.	Drug: Crenezumab; Crenezumab was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale Score [Baseline, Week 77]

   The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline for this primary endpoint. Data after 29 January 2019 are censored for the primary and secondary efficacy analyses to avoid potential biases due to investigators, participants, raters, etc. being potentially influenced by early closure of the study due to lack of efficacy.

Secondary Outcome Measures

1. Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score [Baseline, Week 77]

   The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

2. Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score [Baseline, Week 77]

   The ADAS-Cog-11 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The score range for ADAS-Cog-11 is from 0 to 70 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

3. Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS) [Baseline, Week 77]

   The CDR-GS represents a semi-structured interview which rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care) on a 5-point scale in which CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

4. Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE) [Baseline, Week 77]

   The MMSE is a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target 6 areas: orientation, registration, attention, short-term recall, language and constructional praxis/visuospatial abilities. The scores on the MMSE range from 0 to 30, with higher scores indicating better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

5. Change From Baseline to Week 77 on Function as Assessed by (ADCS-ADL) Total Score [Baseline, Week 77]

   The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

6. Change From Baseline to Week 77 on Function as Assessed by (ADCS-iADL) Instrumental Score [Baseline, Week 77]

   The ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) measures activities such as using the telephone, managing finances and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

7. Change From Baseline to Week 77 on Function as Assessed by the Functional Activities Questionnaire (FAQ) Total Score [Baseline, Week 77]

   The Functional Activities Questionnaire (FAQ) is an instrument consisting of 10 items and assesses instrumental, social and cognitive functioning. The score range is from 0 to 30 with higher scores representing higher impairment. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

8. Change From Baseline to Week 77 on a Measure of Dependence Level Assessed From the ADCS-ADL Score [Baseline, Week 77]

   The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

9. Change From Baseline to Week 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score [Baseline, Week 53]

   The NPI-Q evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavioral disturbances and appetite/eating abnormalities. The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, moderate and marked). The total severity score range is from 0 to 36 with higher scores representing higher severity. Difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures adjusting for disease severity, APOEe4 status, geographic region and the use/non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

10. Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score [Baseline, Week 77]

    The QoL-AD (Quality of Life - Alzheimer's Disease) scale assesses QoL in participants who have dementia. The QoL-AD consists of 13 items covering aspects of participants' relationships with friends and family, physical condition, mood, concerns about finances and overall assessment of QoL. Items are rated on 4-point Likert-type scales ranging from 1 [poor] to 4 [excellent]. The score range is from 13 to 52, with higher scores indicating a better QoL. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

11. Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score [Baseline, Week 53]

    The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally designed to reflect the stresses experienced by caregivers of people with dementia. This modified version includes slight modifications in item and title wording (e.g., removal of "your relative" to refer directly to the patient, removal of "burden" from title) and the use of 11-point numerical rating scales. The ZCI-AD scale consists of a total of 30 items. Total scores will be calculated with a total score range from 0 to 300 (higher scores indicate a higher burden on the caregiver). The difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

12. European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Participants [Baseline, Week 77]

    The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

13. European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Caregivers [Baseline, Week 77]

    The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

14. Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs) [Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).]

    An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

15. Percentage of Participants With Anti-Crenezumab Antibodies [Baseline up to Week 105]

    Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Crenezumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.

16. Serum Concentration of Crenezumab [Pre-infusion (0 hour), 60-90 minutes post-infusion on Day 1 Week 1 and on Week 25; Weeks 13 (Pre-dose), 37 (Pre-dose), 53 (Pre-dose) and 77 (Pre-dose) (infusion length = as per the Pharmacy Manual)]

    Serum concentration data for Crenezumab will be tabulated and summarized. Descriptive summary statistics will include the arithmetic mean and SD. Since a sparse PK sampling design is being used, population (non-linear mixed-effects) modeling will be used to analyze the dose concentration-time data of crenezumab. Information from other clinical studies may be incorporated to establish the PK model. Please note that Post-dose samples were not collected at Weeks 5, 13, 37, 53 and 77.

17. Plasma Amyloid Beta (Abeta) 40 Concentrations [Week 1 Day 1; Weeks 53]

    Plasma Abeta 40 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53.

18. Plasma Amyloid Beta (Abeta) 42 Concentrations [Week 1 Day 1; Weeks 53]

    Plasma Abeta 42 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53.

19. Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI) [Baseline, Week 105]

    Percentage Change in Whole Brain Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

20. Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI) [Baseline, Week 105]

    Percentage Change in Ventricle Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

21. Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI) [Baseline, Week 105]

    Percentage Change in Hippocampal Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Weight between 40 and 120 kilograms (Kg) inclusive

• Availability of a person (referred to as the "caregiver") who in the investigator's judgment:

• Has frequent and sufficient contact with the participant to be able to provide accurate information regarding the participant's cognitive and functional abilities, agrees to provide information at clinic visits (which require partner input for scale completion), signs the necessary consent form, and has sufficient cognitive capacity to accurately report upon the participant's behavior and cognitive and functional abilities

• Fluency in the language of the tests used at the study site

• Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)

• Evidence of the AD pathological process, by a positive amyloid assessment either on cerebrospinal fluid (CSF) amyloid beta 1-42 levels as measured on the Elecsys beta-amyloid(1-42) test system or amyloid PET scan by qualitative read by the core/central PET laboratory

• Demonstrated abnormal memory function at screening (up to 4 weeks before screening begins) or screening (FCSRT cueing index =<0.67 AND free recall =<27)

• Screening mini mental state examination (MMSE) score of greater than or equal to (>=) 22 points and Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1.0

• Meets National Institute on Aging/Alzheimer's Association (NIAAA) core clinical criteria for probable AD dementia or prodromal AD (consistent with the NIAAA diagnostic criteria and guidelines for mild cognitive impairment (MCI)

• If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening

• Participant must have completed at least 6 years of formal education after the age of 5 years

Exclusion Criteria:

• Any evidence of a condition other than AD that may affect cognition such as other dementias, stroke, brain damage, autoimmune disorders (e.g. multiple sclerosis) or infections with neurological sequelae.

• History of major psychiatric illness such as schizophrenia or major depression (if not considered in remission)

• At risk of suicide in the opinion of the investigator

• Any abnormal MRI findings, such as presence of cerebral vascular pathology, cortical stroke, etc or inability to tolerate MRI procedures or contraindication to MRI

• Unstable or clinically significant cardiovascular (e.g., myocardial infarction), kidney or liver disease

• Uncontrolled hypertension

• Screening hemoglobin A1c (HbA1C) >8%

• Poor peripheral venous access

• History of cancer except:

If considered to be cured or If not being actively treated with anti-cancer therapy or radiotherapy

• Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Imaging End Points Clinical Research	Scottsdale	Arizona	United States	85258
2	Health Initiatives Research, PLLC	Fayetteville	Arkansas	United States	72703
3	Clinical Trials Inc.	Little Rock	Arkansas	United States	72205
4	Neuro-Therapeutics Inc.	Pasadena	California	United States	91105
5	Desert Valley Medical Group	Rancho Mirage	California	United States	92270
6	Anderson Clinical Research, Inc.	Redlands	California	United States	92374
7	University of California, Davis; Alzheimers Disease Center, Department of Neurology	Sacramento	California	United States	95817
8	UCSF - Memory and Aging Center	San Francisco	California	United States	94158
9	MCB Clinical Research Centers	Colorado Springs	Colorado	United States	80910
10	Research Center for Clinical Studies, Inc.	Norwalk	Connecticut	United States	06851
11	KI Health Partners, LLC; New England Institute for Clinical Research	Stamford	Connecticut	United States	06905
12	Georgetown University Hospital	Washington	District of Columbia	United States	20057
13	JEM Research LLC	Atlantis	Florida	United States	33462
14	Bradenton Research Center	Bradenton	Florida	United States	34205
15	Neuropsychiatric Research; Center of Southwest Florida	Fort Myers	Florida	United States	33912
16	Alzheimer's Research and Treatment Center	Lake Worth	Florida	United States	33414
17	Renstar Medical Research	Ocala	Florida	United States	34470
18	Bioclinica Research	Orlando	Florida	United States	32806
19	Progressive Medical Research	Port Orange	Florida	United States	32127
20	Columbus Memory Center	Columbus	Georgia	United States	31909
21	Lake Charles Clinical Trials, LLC	Lake Charles	Louisiana	United States	70601
22	Alzheimers Disease Center; Neurology	Winchester	Massachusetts	United States	01890
23	Health Partners Institute for Education and Research	Saint Paul	Minnesota	United States	55130
24	Precise Research Centers	Flowood	Mississippi	United States	39232
25	University of Nebraska Medical Center; Dept of Neurological Sciences	Omaha	Nebraska	United States	68198-8440
26	Cleveland Clinic Lou Ruvo; Center for Brain Research	Las Vegas	Nevada	United States	89106
27	The Cognitive and Research Center of New Jersey	Summit	New Jersey	United States	07081
28	Advanced Memory Research Institute of NJ	Toms River	New Jersey	United States	08755
29	Columbia University Medical Center	New York	New York	United States	10032
30	Burke Rehabilitation Hospital	White Plains	New York	United States	10605
31	Behavioral Health Research	Charlotte	North Carolina	United States	28211
32	Wake Research Associates	Raleigh	North Carolina	United States	27612
33	University of Cincinnati; Department of Psychiatry and Behavioral Neuroscience	Cincinnati	Ohio	United States	45219
34	Ohio State University; College of Medicine	Columbus	Ohio	United States	43210
35	Dayton Center for Neuro Disorders	Dayton	Ohio	United States	45459
36	Summit Research Network Inc.	Portland	Oregon	United States	97210
37	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
38	Northeastern Pennsylvania Memory	Plains	Pennsylvania	United States	18705
39	Abington Neurological Associates	Willow Grove	Pennsylvania	United States	19090
40	Neurology Clinic PC	Cordova	Tennessee	United States	38018
41	Senior Adults Specialty Research	Austin	Texas	United States	78757
42	Gadolin Research, LLC	Beaumont	Texas	United States	77702
43	Texas Neurology PA	Dallas	Texas	United States	75214
44	Kerwin Research Center, LLC	Dallas	Texas	United States	75231
45	Alzheimers Disease & Memory Disorders Center; Department of Neurology Baylor College of Medicine	Houston	Texas	United States	77030
46	Clinical Trials of Texas, Inc	San Antonio	Texas	United States	78229
47	Sentara Medical Group	Norfolk	Virginia	United States	23507
48	National Clinical Research Inc.-Richmond	Richmond	Virginia	United States	23294
49	Hospital Italiano	Buenos Aires		Argentina	C1181ACH
50	Universidad Maimonides	Caba		Argentina	C1405BCK
51	DAMIC	Cordoba		Argentina	X500 3DCE
52	St Vincent's Hospital Sydney	Darlinghurst	New South Wales	Australia	2010
53	Central Coast Neurosciences Research	Erina	New South Wales	Australia	2250
54	Hornsby Ku-ring-gai Hospital; Division of Rehabilitation & Aged Care	Hornsby	New South Wales	Australia	2077
55	The Queen Elizabeth Hospital; Neurology	Woodville	South Australia	Australia	5011
56	AZ Sint Jan	Brugge		Belgium	8000
57	AZ Groeninge	Kortrijk		Belgium	8500
58	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
59	CCBR - Brasilia	Brasilia	DF	Brazil	70200-730
60	Hospital das Clinicas - UFMG	Belo Horizonte	MG	Brazil	31270-901
61	Instituto de Neurologia de Curitiba	Curitiba	PR	Brazil	81210-310
62	Centro Psiquiatria Sandra Ruschel Ltda	Rio de Janeiro	RJ	Brazil	22270-060
63	Hospital das Clinicas - UFRGS	Porto Alegre	RS	Brazil
64	Clínica Dr. Norton Sayeg LTDA - EPP	Sao Paulo	SP	Brazil	04534-011
65	OCT Research ULC	Kelowna	British Columbia	Canada	V1Y 1Z9
66	Vancouver Island Health Authority	Victoria	British Columbia	Canada	V8R 1J8
67	True North Clinical Research-Halifax	Halifax	Nova Scotia	Canada	B3S 1M7
68	True North Clinical Research Kentville	Kentville	Nova Scotia	Canada	B4N 5E3
69	Providence Care; Mental Health Services	Kingston	Ontario	Canada	K7L 4X3
70	Parkwood Hospital; Geriatric Medicine	London	Ontario	Canada	N6C 5J1
71	Kawartha Centre - Redefining Healthy Aging	Peterborough	Ontario	Canada	K9H 2P4
72	The Centre for Memory and Aging	Toronto	Ontario	Canada	M4G 3E8
73	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1N9
74	Devonshire Clinical Research Inc.	Woodstock	Ontario	Canada	N4S 5P5
75	Clinique Neuro Rive-Sud	Greenfield Park	Quebec	Canada	J4V 2J2
76	ALPHA Recherche Clinique	Quebec		Canada	G3K 2P8
77	Beijing Union Hospital	Beijing		China	100730
78	Tianjin Medical University General Hospital	Tianjin (天津)		China	300052
79	Aarhus Universitetshospital, Neurologisk Afdeling F, Demensklinikken	Aarhus N		Denmark	8200
80	Rigshospitalet, Hukommelsesklinikken	København Ø		Denmark	2100
81	Laane-Tallinna Keskhaigla	Tallinn		Estonia	10617
82	Hopital Pellegrin; Cmrr Aquitaine	Bordeaux		France	33076
83	Hôpital de Jour du Centre pour Personnes Âgées; Louis Pasteur Neurologie	Colmar		France	68000
84	Hopital Roger Salengro; Service de Neurologie	Lille		France
85	CHU de Limoges Hopital Dupuytren; Service de Medecine Geriatrique	Limoges		France	87042
86	Hopital Broca	Paris		France	75013
87	CH Pitie Salpetriere; IM2A	Paris		France	75651
88	Hôpital Maison Blanche	Reims		France	51092
89	CHU Rennes - Hopital Pontchaillou	Rennes		France	35033
90	CHU de Rouen Hopital; Service de Neurologie	Rouen		France	76031
91	Hop Guillaume Et Rene Laennec; Cmrr St Herblain	St Herblain		France	44800
92	Hopital des Charpennes	Villeurbanne		France	69100
93	ECRC Experimental and Clinical Research Center, Charité Campus Berlin Buch, Memory Clinic	Berlin		Germany	13125
94	Klinikum Joh.Wolfg.Goethe-UNI Zentrum d. Psychiatrie Klinik f. Psychiatrie Psychosomatik	Frankfurt		Germany	60528
95	Universitätsklinikum Freiburg, Zentrum für Geriatrie und Gerontologie	Freiburg		Germany	79106
96	Universitätsklinikum des Saarlandes Klinik f. Psychiatrie und Psychotherapie	Homburg/Saar		Germany	66421
97	PANAKEIA - Arzneimittelforschung Leipzig GmbH	Leipzig		Germany	04275
98	Pharmakologisches Studienzentrum	Mittweida		Germany	09648
99	Klinikum rechts der Isar der TU München; Klinik für Psychiatrie und Psychotherapie	München		Germany	81675
100	Rambam Medical Center	Haifa		Israel	3109601
101	Sheba Medical Center; Psychiatry Department	Ramat Gan		Israel	5262100
102	Tel Aviv Sourasky Medical Center; Department of Neurology	Tel Aviv		Israel	6423906
103	Azienda Ospedaliera Universitaria Policlinico Tor Vergata; Neurologia	Roma	Lazio	Italy	00133
104	Umberto I Policlinico di Roma-Università di Roma La Sapienza	Roma	Lazio	Italy	00185
105	Ospedale San Giovanni Calibita Fatebenefratell;Neurologia	Roma	Lazio	Italy	00186
106	IRCCS "Centro S. Giovanni di Dio" Fatebenefratelli -UO Alzheimer	Brescia	Lombardia	Italy	25125
107	Irccs Multimedica Santa Maria; Unita' Di Neurologia	Castellanza	Lombardia	Italy	21053
108	IRCCS Ospedale San Raffaele; Centro Disturbi della Memoria	Milano	Lombardia	Italy	20132
109	Fondazione IRCCS Istituto Nazionale Neurologico Besta; UO Neuropatologia	Milano	Lombardia	Italy	20133
110	Ospedale S. Maria Nascente; Fondazione Don Gnocchi; Dip. Neurologia Riabilitativa	Milano	Lombardia	Italy	20148
111	Ospedale Casati Passirana di Rho; Centro Regionale Alzheimer	Passirana	Lombardia	Italy	20017
112	IRCCS Neuromed; Neurologia I-Centro studio e cura delle demenze e UVA	Pozzilli	Molise	Italy	86077
113	AO Città della Salute e della Scienza Osp.S.Giov.Battista Molinette; SC Geriatria	Torino	Piemonte	Italy	10126
114	A.O. Universitaria Pisana; Neurologia	Pisa	Toscana	Italy	56126
115	National Center for Geriatrics and Gerontology	Aichi		Japan	474-8511
116	Inage Neurology and Memory Clinic	Chiba		Japan	263-0043
117	Fukuoka Mirai Hospital	Fukuoka		Japan	813-0017
118	National Hospital Organization Hiroshima-Nishi Medical Center	Hiroshima		Japan	739-0696
119	Tsukazaki Hospital	Hyogo		Japan	671-1227
120	Iwate Medical University Hospital	Iwate		Japan	028-3695
121	Kagawa Prefectural Central Hospital	Kagawa		Japan	760-8557
122	Fujisawa City Hospital	Kanagawa		Japan	251-8550
123	National Hospital Organization Sagamihara National Hospital	Kanagawa		Japan	252-0392
124	Ijinkai Takeda General Hospital	Kyoto		Japan	601-1495
125	Rakuwakai Otowarehabilitation Hospital	Kyoto		Japan	607-8113
126	National Hospital Organization Matsumoto Medical Center	Nagano		Japan	399-8701
127	Katayama Medical Clinic	Okayama		Japan	710-0813
128	Osaka University Hospital	Osaka		Japan	565-0871
129	Asakayama General Hospital	Osaka		Japan	590-0018
130	NHO Shizuoka Institute of Epilepsy and Neurological Disorders	Shizuoka		Japan	420-8688
131	Kanto Central Hospital	Tokyo		Japan	158-8531
132	Tokyo Medical University Hospital	Tokyo		Japan	160-0023
133	Shinjuku Research Park Clinic	Tokyo		Japan	169-0073
134	Tokyo Metropolitan Geriatric Hospital	Tokyo		Japan	173-0015
135	National Center of Neurology and Psychiatry	Tokyo		Japan	187-8551
136	Tokyo Medical University Hachioji Medical Center	Tokyo		Japan	193-0998
137	Dong-A University Hospital	Busan		Korea, Republic of	49201
138	Gachon University Gil Medical Center	Incheon		Korea, Republic of	21565
139	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	13605
140	Seoul National University Hospital	Seoul		Korea, Republic of	03080
141	Hanyang University Seoul Hospital	Seoul		Korea, Republic of	04763
142	Konkuk University Medical Center	Seoul		Korea, Republic of	05030
143	Samsung Medical Center	Seoul		Korea, Republic of	06351
144	Seoul St Mary's Hospital	Seoul		Korea, Republic of	06591
145	Borame Medical Center	Seoul		Korea, Republic of	07061
146	Akershus universitetssykehus HF; Nevroklinikken S203	Lørenskog		Norway	1478
147	Oslo universitetssykehus HF Ullevål sykehus; Hukommelsesklinikken	Oslo		Norway	0450
148	Clinica Internacional; Unidad De Investigacion	Lima		Peru	15001
149	Hospital Nacional Dos de Mayo; Unidad de Investigacion de Neurologia	Lima		Peru	Lima 01
150	NZOZ Dom Sue Ryder	Bydgoszcz		Poland	85-023
151	Centrum Medyczne Euromedis Sp. z o.o.	Szczecin		Poland	70-111
152	Centrum Medyczne NeuroProtect	Warszawa		Poland	01-684
153	NZOZ WCA	Wrocław		Poland	53-659
154	Hospital de Braga; Servico de Neurologia	Braga		Portugal	4710-243
155	HUC; Servico de Neurologia	Coimbra		Portugal	3000-075
156	Hospital Pedro Hispano; Servico de Neurologia	Matosinhos		Portugal	4464-513
157	Hospital Geral de Santo Antonio; Servico de Neurologia	Porto		Portugal	4099-001
158	LLC Baltic Medicine	Saint-Petersburg	Sankt Petersburg	Russian Federation	194356
159	State Healthcare Institution of Sverdlovsk Region Sverdlovsk Regional Clinical Psychiatric Hospita	Ekaterinburg	Sverdlovsk	Russian Federation	620030
160	State Autonomous Healthcare Institution "Republican Clinical Neurological Center	Kazan		Russian Federation	420021
161	State autonomous institution of healthcare Inter-regional clinical and diagnostic center	Kazan		Russian Federation	420101
162	Institution of RAMS (Mental Health Research Center of RAMS)	Moscow		Russian Federation	115522
163	City Clinical Psychiatry Hospital #1	Nizhny Novgorod		Russian Federation	603155
164	St Nicolas Psychiatric Hospital; Chair of Psychiatry and Narcology of St. Petersburg Medical Academy	St Petersburg		Russian Federation	190121
165	Nebbiolo Center for Clinical Trials	Tomsk		Russian Federation	634009
166	Clinic for Mental disorders Dr Laza Lazarevic	Belgrade		Serbia	11000
167	Neurology clinic, Clinical Center of Serbia	Belgrade		Serbia	11000
168	Clinic for neurology, Clinical Center Kragujevac	Kragujevac		Serbia	34000
169	Private Practice; the Osteoporosis Clinic	Johannesburg		South Africa	2196
170	Hospital General Universitario de Elche; Servicio de Neurología	Elche	Alicante	Spain	03203
171	Fundació ACE	BArcelon	Barcelona	Spain	08034
172	Hospital General De Catalunya; Servicio de Neurologia	Sant Cugat del Valles	Barcelona	Spain	8195
173	Hospital Mutua De Terrasa; Servicio de Neurologia	Terrassa	Barcelona	Spain	08222
174	Hospital Virgen del Puerto. Servicio de Neurología	Plasencia	Caceres	Spain	10600
175	Hospital Universitario Marques de Valdecilla; Servicio de Neurología	Santander	Cantabria	Spain
176	Hospital Santa Caterina, Unitat de Valoració de la memoria i les demencies	Salt	Girona	Spain	17090
177	Policlínica Guipuzkoa; Servicio de Neurología	Donosti-San Sebastián	Guipuzcoa	Spain	20014
178	Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Neurologia	Santiago de Compostela	LA Coruña	Spain	15706
179	Hospital San Pedro; Servicio de Neurología	Logroño	LA Rioja	Spain	26006
180	Hospital Quiron de Madrid; Servicio de Neurologia	Pozuelo de Alarcon	Madrid	Spain	28223
181	Clinica Universitaria de Navarra; Servicio de Neurología	Pamplona	Navarra	Spain	31008
182	CAE Oroitu	BaraKaldo	Vizcaya	Spain	48903
183	Hospital Perpetuo Socorro, Servicio de Geriatria	Albacete		Spain	2006
184	Hospital de la Santa Creu i Sant Pau; Servicio de Neurologia	Barcelona		Spain	08025
185	Hospital Universitario de Burgos. Servicio de Neurología	Burgos		Spain	09006
186	Hospital la Magdalena; Servicio de Neurologia	Castellon		Spain	12004
187	Hospital Universitario Reina Sofia; Servicio de Neurologia	Cordoba		Spain	14011
188	Hospital Ramon y Cajal; Servicio de Neurologia	Madrid		Spain	28034
189	Complejo Asistencial Universitario de Salamanca; Servicio de Psiquiatría; CSM La Alamedilla	Salamanca		Spain	37005
190	Hospital Universitario Virgen Macarena; Servicio de Neurologia	Sevilla		Spain	41009
191	Skånes Universitetssjukhus Malmö, Minneskliniken	Malmö		Sweden	211 46
192	Sahlgrenska Academy University,Neuroscience and Physiology;Departmt of Psychiatry and Neurochemistry	Mölndal		Sweden	431 41
193	Changhua Christian Hospital; Neurology	Changhua County		Taiwan	500
194	Kaohsiung Medical University Hospital; Neurology	Kaohsiung		Taiwan	807
195	Taipei Medical University - Shuang Ho Hospital - Neurology	New Taipei City		Taiwan	23561
196	National Taiwan University Hospital; Neurology	Taipei		Taiwan	100
197	Chang Gung Memorial Foundation - Linkou - Neurology	Taoyuan		Taiwan	333
198	Hacettepe University Medical Faculty; Neurology	Ankara		Turkey	06100
199	Istanbul University Istanbul School of Medicine; Neurology	Istanbul		Turkey	34093
200	Ondokuz Mayis Univ. Med. Fac.; Neurology	Samsun		Turkey	55139
201	The Fritchie Centre, Charlton Lane Centre, Charlon Lane, Leckhampton; The Fritchie Centre	Cheltenham		United Kingdom	GL53 9DZ
202	Surrey and Borders NHS Foundation Trust; Brain Science Research Unit	Chertsey		United Kingdom	KT16 0AE
203	Sussex Partnership NHS Foundation Trust; Cognitive Treatment and Research unit	Crowborough		United Kingdom	TN6 1HB
204	Ninewells Hospital	Dundee		United Kingdom	DD12 9SY
205	NHS Lothian - Western General Hospital; NHS Lothian - Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
206	Queen Elizabeth University Hospital; Clinical Research Facility	Glasgow		United Kingdom	G51 4TF
207	RE:Cognition Health	London		United Kingdom	W1G 9RU
208	Charing Cross Hospital; Imperial Memory Unit, Level 10 West	London		United Kingdom	W6 8RF
209	Manchester Royal Infirmary	Manchester		United Kingdom	M13 9WL
210	John Radcliffe Hospital	Oxford		United Kingdom	OX3 9DU
211	University Southampton NHS Foundation Trust; Wessex Neurologica Centre	Southampton		United Kingdom	SO166YD

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 14, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03114657
• Other Study ID Numbers: BN29553; 2016-003288-20
• First Posted: Apr 14, 2017
• Last Update Posted: Jul 16, 2020
• Last Verified: Jun 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Recruitment Details	The study was conducted at 209 centers in 27 countries.
Pre-assignment Detail	A total of 806 participants were enrolled at 209 centers. 4 participants did not receive any study treatment meaning that the modified intent-to-treat and safety populations consisted of 802 participants.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Period Title: Overall Study
STARTED	399	407
COMPLETED	0	0
NOT COMPLETED	399	407

Baseline Characteristics

Arm/Group Title	Placebo	Crenezumab	Total
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.	Total of all reporting groups
Overall Participants	399	407	806
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	70.7 (7.9)	71.1 (7.5)	70.9 (7.7)
Sex: Female, Male (Count of Participants)
Female	225 56.4%	231 56.8%	456 56.6%
Male	174 43.6%	176 43.2%	350 43.4%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	42 10.5%	35 8.6%	77 9.6%
Not Hispanic or Latino	334 83.7%	348 85.5%	682 84.6%
Not Stated	15 3.8%	19 4.7%	34 4.2%
Unknown	8 2%	5 1.2%	13 1.6%
Race/Ethnicity, Customized (Number) [Number]
American Indian or Alaska Native	8 2%	5 1.2%	13 1.6%
Asian	45 11.3%	47 11.5%	92 11.4%
Black or African American	4 1%	3 0.7%	7 0.9%
Multiple	4 1%	3 0.7%	7 0.9%
Unknown	5 1.3%	7 1.7%	12 1.5%
White	333 83.5%	342 84%	675 83.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale Score
Description	The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline for this primary endpoint. Data after 29 January 2019 are censored for the primary and secondary efficacy analyses to avoid potential biases due to investigators, participants, raters, etc. being potentially influenced by early closure of the study due to lack of efficacy.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	3.19 (0.434)	1.89 (0.471)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.00 to 2.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.633
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score
Description	The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	8.90 (1.382)	7.16 (1.526)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; -2.40 to 5.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.028
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score
Description	The ADAS-Cog-11 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The score range for ADAS-Cog-11 is from 0 to 70 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	7.16 (1.452)	6.84 (1.592)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; -4.03 to 4.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.124
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS)
Description	The CDR-GS represents a semi-structured interview which rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care) on a 5-point scale in which CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	0.39 (0.096)	0.29 (0.102)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.20 to 0.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE)
Description	The MMSE is a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target 6 areas: orientation, registration, attention, short-term recall, language and constructional praxis/visuospatial abilities. The scores on the MMSE range from 0 to 30, with higher scores indicating better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	-3.63 (0.672)	-3.21 (0.740)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -2.42 to 1.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.985
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to Week 77 on Function as Assessed by (ADCS-ADL) Total Score
Description	The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	-8.83 (2.064)	-6.31 (2.278)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.52
	Confidence Interval	(2-Sided) 95%; -8.74 to 3.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.052
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to Week 77 on Function as Assessed by (ADCS-iADL) Instrumental Score
Description	The ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) measures activities such as using the telephone, managing finances and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	-6.69 (1.692)	-5.51 (1.872)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.19
	Confidence Interval	(2-Sided) 95%; -6.29 to 3.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.501
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline to Week 77 on Function as Assessed by the Functional Activities Questionnaire (FAQ) Total Score
Description	The Functional Activities Questionnaire (FAQ) is an instrument consisting of 10 items and assesses instrumental, social and cognitive functioning. The score range is from 0 to 30 with higher scores representing higher impairment. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	5.00 (0.991)	4.37 (1.059)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; -2.25 to 3.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.420
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline to Week 77 on a Measure of Dependence Level Assessed From the ADCS-ADL Score
Description	The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

Please note that for this Outcome Measure, no participants were evaluated at all as the derivation of this endpoint was not pre-specified before the Sponsor terminated the study and therefore it was not reported.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	0	0

10. Secondary Outcome

Title	Change From Baseline to Week 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score
Description	The NPI-Q evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavioral disturbances and appetite/eating abnormalities. The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, moderate and marked). The total severity score range is from 0 to 36 with higher scores representing higher severity. Difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures adjusting for disease severity, APOEe4 status, geographic region and the use/non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 53

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	102	110
Least Squares Mean (Standard Error) [Units on a Scale]	-0.00 (0.852)	0.76 (0.886)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -1.75 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.502
	Estimation Comments

11. Secondary Outcome

Title	Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score
Description	The QoL-AD (Quality of Life - Alzheimer's Disease) scale assesses QoL in participants who have dementia. The QoL-AD consists of 13 items covering aspects of participants' relationships with friends and family, physical condition, mood, concerns about finances and overall assessment of QoL. Items are rated on 4-point Likert-type scales ranging from 1 [poor] to 4 [excellent]. The score range is from 13 to 52, with higher scores indicating a better QoL. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	11
Least Squares Mean (Standard Error) [Units on a Scale]	-1.61 (1.310)	-1.16 (1.432)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -3.30 to 2.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.383
	Estimation Comments

12. Secondary Outcome

Title	Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score
Description	The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally designed to reflect the stresses experienced by caregivers of people with dementia. This modified version includes slight modifications in item and title wording (e.g., removal of "your relative" to refer directly to the patient, removal of "burden" from title) and the use of 11-point numerical rating scales. The ZCI-AD scale consists of a total of 30 items. Total scores will be calculated with a total score range from 0 to 300 (higher scores indicate a higher burden on the caregiver). The difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 53

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	101	108
Least Squares Mean (Standard Error) [Units on a Scale]	9.20 (9.292)	2.65 (9.643)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	6.55
	Confidence Interval	(2-Sided) 95%; -4.35 to 17.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.527
	Estimation Comments

13. Secondary Outcome

Title	European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Participants
Description	The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	-3.69 (3.961)	-3.39 (4.392)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -12.31 to 11.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.831
	Estimation Comments

14. Secondary Outcome

Title	European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Caregivers
Description	The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 77

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	15	12
Least Squares Mean (Standard Error) [Units on a Scale]	-4.07 (2.724)	-0.68 (3.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.38
	Confidence Interval	(2-Sided) 95%; -11.50 to 4.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.940
	Estimation Comments

15. Secondary Outcome

Title	Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs)
Description	An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time Frame	Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).

Outcome Measure Data

Analysis Population Description

The Safety analysis population included all randomized participants who received at least 1 dose of study drug with participants grouped according to actual treatment received. If a participant received at least 2 vials of crenezumab, then they were placed in the crenezumab arm.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	398	404
AEs	73.1	73.5
SAEs	10.6	8.2

16. Secondary Outcome

Title	Percentage of Participants With Anti-Crenezumab Antibodies
Description	Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Crenezumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.
Time Frame	Baseline up to Week 105

Outcome Measure Data

Analysis Population Description

Please note that for this Outcome Measure, no Participants were evaluated at all as the existing immunogenicity data from an identical study (Study BN29552) showed a low potential of Crenezumab to induce Anti-Drug Antibodies (ADAs).

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	0	0

17. Secondary Outcome

Title	Serum Concentration of Crenezumab
Description	Serum concentration data for Crenezumab will be tabulated and summarized. Descriptive summary statistics will include the arithmetic mean and SD. Since a sparse PK sampling design is being used, population (non-linear mixed-effects) modeling will be used to analyze the dose concentration-time data of crenezumab. Information from other clinical studies may be incorporated to establish the PK model. Please note that Post-dose samples were not collected at Weeks 5, 13, 37, 53 and 77.
Time Frame	Pre-infusion (0 hour), 60-90 minutes post-infusion on Day 1 Week 1 and on Week 25; Weeks 13 (Pre-dose), 37 (Pre-dose), 53 (Pre-dose) and 77 (Pre-dose) (infusion length = as per the Pharmacy Manual)

Outcome Measure Data

Analysis Population Description

The PK Analysis population was defined as all participants who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	138
Week 1 Day 1 Predose	NA (NA)
Week 1 Day 1 Postdose	1260 (437)
Week 5 Predose	246 (128)
Week 13 Predose	360 (162)
Week 25 Predose	401 (196)
Week 25 Postdose	1650 (443)
Week 37 Predose	456 (351)
Week 53 Predose	401 (130)
Week 77 Predose	357 (94.2)

18. Secondary Outcome

Title	Plasma Amyloid Beta (Abeta) 40 Concentrations
Description	Plasma Abeta 40 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53.
Time Frame	Week 1 Day 1; Weeks 53

Outcome Measure Data

Analysis Population Description

The PD Analysis population was defined as all participants who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	36
Week 1 Day 1 Predose	0.415 (0.0687)
Week 53 Predose	46.6 (6.91)

19. Secondary Outcome

Title	Plasma Amyloid Beta (Abeta) 42 Concentrations
Description	Plasma Abeta 42 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53.
Time Frame	Week 1 Day 1; Weeks 53

Outcome Measure Data

Analysis Population Description

The PD Analysis population was defined as all participants who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	36
Week 1 Day 1 Predose	0.0331 (0.00463)
Week 53 Predose	2.94 (0.473)

20. Secondary Outcome

Title	Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI)
Description	Percentage Change in Whole Brain Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 105

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	4	4
Least Squares Mean (Standard Error) [Percentage]	-2.71 (0.444)	-2.15 (0.345)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -2.01 to 0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.622
	Estimation Comments

21. Secondary Outcome

Title	Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI)
Description	Percentage Change in Ventricle Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 105

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	4	4
Least Squares Mean (Standard Error) [Percentage]	18.78 (1.343)	17.18 (1.145)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95%; -1.70 to 4.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.668
	Estimation Comments

22. Secondary Outcome

Title	Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI)
Description	Percentage Change in Hippocampal Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time Frame	Baseline, Week 105

Outcome Measure Data

Analysis Population Description

The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.

Arm/Group Title	Placebo	Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.	Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Measure Participants	2	2
Least Squares Mean (Standard Error) [Percentage]	-6.34 (0.338)	-5.98 (0.290)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Crenezumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -1.13 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.373
	Estimation Comments

Adverse Events

Time Frame	Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).
Arm/Group Title	Placebo		Crenezumab
Arm/Group Description	Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.		Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
All Cause Mortality
	Placebo		Crenezumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/398 (1.5%)		0/404 (0%)
Serious Adverse Events
	Placebo		Crenezumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/398 (10.6%)		33/404 (8.2%)
Blood and lymphatic system disorders
ANAEMIA	1/398 (0.3%)	1	2/404 (0.5%)	2
Cardiac disorders
ATRIAL FIBRILLATION	2/398 (0.5%)	2	0/404 (0%)	0
CORONARY ARTERY DISEASE	1/398 (0.3%)	1	0/404 (0%)	0
PALPITATIONS	0/398 (0%)	0	1/404 (0.2%)	1
TACHYCARDIA	0/398 (0%)	0	1/404 (0.2%)	1
TRIFASCICULAR BLOCK	0/398 (0%)	0	1/404 (0.2%)	1
Ear and labyrinth disorders
TINNITUS	1/398 (0.3%)	1	0/404 (0%)	0
VERTIGO	2/398 (0.5%)	2	0/404 (0%)	0
Gastrointestinal disorders
COLITIS ISCHAEMIC	1/398 (0.3%)	1	0/404 (0%)	0
CONSTIPATION	1/398 (0.3%)	1	0/404 (0%)	0
GASTROINTESTINAL HAEMORRHAGE	1/398 (0.3%)	1	0/404 (0%)	0
UPPER GASTROINTESTINAL HAEMORRHAGE	1/398 (0.3%)	1	0/404 (0%)	0
General disorders
ASTHENIA	1/398 (0.3%)	1	0/404 (0%)	0
CHEST DISCOMFORT	0/398 (0%)	0	1/404 (0.2%)	1
CHEST PAIN	0/398 (0%)	0	1/404 (0.2%)	1
NON-CARDIAC CHEST PAIN	0/398 (0%)	0	1/404 (0.2%)	1
PYREXIA	1/398 (0.3%)	1	0/404 (0%)	0
SUDDEN DEATH	2/398 (0.5%)	2	0/404 (0%)	0
Infections and infestations
BACTERAEMIA	1/398 (0.3%)	1	0/404 (0%)	0
BRONCHITIS	0/398 (0%)	0	1/404 (0.2%)	1
CELLULITIS STAPHYLOCOCCAL	1/398 (0.3%)	1	0/404 (0%)	0
CLOSTRIDIUM DIFFICILE INFECTION	1/398 (0.3%)	1	0/404 (0%)	0
ENDOCARDITIS	0/398 (0%)	0	1/404 (0.2%)	1
ENTEROBACTER PNEUMONIA	1/398 (0.3%)	1	0/404 (0%)	0
GASTROENTERITIS	2/398 (0.5%)	2	0/404 (0%)	0
LIVER ABSCESS	0/398 (0%)	0	1/404 (0.2%)	1
NEUROSYPHILIS	0/398 (0%)	0	1/404 (0.2%)	1
PHARYNGITIS STREPTOCOCCAL	0/398 (0%)	0	1/404 (0.2%)	1
PNEUMONIA	2/398 (0.5%)	2	1/404 (0.2%)	1
PNEUMONIA INFLUENZAL	0/398 (0%)	0	1/404 (0.2%)	1
STAPHYLOCOCCAL BACTERAEMIA	1/398 (0.3%)	1	0/404 (0%)	0
URINARY TRACT INFECTION	1/398 (0.3%)	1	0/404 (0%)	0
Injury, poisoning and procedural complications
ANKLE FRACTURE	0/398 (0%)	0	1/404 (0.2%)	1
CLAVICLE FRACTURE	1/398 (0.3%)	1	0/404 (0%)	0
CRANIOCEREBRAL INJURY	1/398 (0.3%)	1	0/404 (0%)	0
FALL	6/398 (1.5%)	6	2/404 (0.5%)	2
HIP FRACTURE	3/398 (0.8%)	3	0/404 (0%)	0
HUMERUS FRACTURE	0/398 (0%)	0	1/404 (0.2%)	1
LOWER LIMB FRACTURE	0/398 (0%)	0	1/404 (0.2%)	1
MENISCUS INJURY	1/398 (0.3%)	1	0/404 (0%)	0
PUBIS FRACTURE	1/398 (0.3%)	1	0/404 (0%)	0
RIB FRACTURE	1/398 (0.3%)	1	1/404 (0.2%)	1
SUBDURAL HAEMATOMA	0/398 (0%)	0	3/404 (0.7%)	3
Investigations
ARTHROSCOPY	0/398 (0%)	0	1/404 (0.2%)	1
Metabolism and nutrition disorders
DEHYDRATION	0/398 (0%)	0	1/404 (0.2%)	1
Musculoskeletal and connective tissue disorders
ARTHRITIS	0/398 (0%)	0	1/404 (0.2%)	1
INTERVERTEBRAL DISC PROTRUSION	0/398 (0%)	0	1/404 (0.2%)	1
MUSCULOSKELETAL PAIN	1/398 (0.3%)	1	0/404 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BONE GIANT CELL TUMOUR MALIGNANT	1/398 (0.3%)	1	0/404 (0%)	0
CLEAR CELL ENDOMETRIAL CARCINOMA	1/398 (0.3%)	1	0/404 (0%)	0
LUNG ADENOCARCINOMA	0/398 (0%)	0	1/404 (0.2%)	1
LUNG NEOPLASM MALIGNANT	0/398 (0%)	0	1/404 (0.2%)	1
PROSTATE CANCER	1/398 (0.3%)	1	0/404 (0%)	0
Nervous system disorders
AMYOTROPHIC LATERAL SCLEROSIS	1/398 (0.3%)	1	0/404 (0%)	0
CEREBRAL ARTERIOSCLEROSIS	1/398 (0.3%)	1	0/404 (0%)	0
ISCHAEMIC CEREBRAL INFARCTION	0/398 (0%)	0	1/404 (0.2%)	1
SPEECH DISORDER	0/398 (0%)	0	1/404 (0.2%)	1
SUBARACHNOID HAEMORRHAGE	0/398 (0%)	0	1/404 (0.2%)	1
SUPERIOR SAGITTAL SINUS THROMBOSIS	1/398 (0.3%)	1	0/404 (0%)	0
SYNCOPE	2/398 (0.5%)	2	0/404 (0%)	0
Psychiatric disorders
AGGRESSION	1/398 (0.3%)	1	0/404 (0%)	0
DELUSION	1/398 (0.3%)	1	0/404 (0%)	0
DEPRESSIVE SYMPTOM	0/398 (0%)	0	1/404 (0.2%)	1
SUICIDE THREAT	0/398 (0%)	0	1/404 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
ASTHMA	1/398 (0.3%)	1	0/404 (0%)	0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0/398 (0%)	0	1/404 (0.2%)	1
COUGH	1/398 (0.3%)	1	0/404 (0%)	0
DYSPNOEA	2/398 (0.5%)	3	0/404 (0%)	0
INTERSTITIAL LUNG DISEASE	1/398 (0.3%)	1	0/404 (0%)	0
PULMONARY EMBOLISM	1/398 (0.3%)	1	1/404 (0.2%)	1
Skin and subcutaneous tissue disorders
SKIN ULCER	0/398 (0%)	0	1/404 (0.2%)	1
Surgical and medical procedures
CARDIAC ABLATION	0/398 (0%)	0	1/404 (0.2%)	1
KNEE ARTHROPLASTY	0/398 (0%)	0	1/404 (0.2%)	1
Vascular disorders
ARTERIOVENOUS FISTULA	1/398 (0.3%)	1	0/404 (0%)	0
HYPERTENSIVE CRISIS	1/398 (0.3%)	1	0/404 (0%)	0
HYPOTENSION	1/398 (0.3%)	1	1/404 (0.2%)	1
PERIPHERAL VASCULAR DISORDER	0/398 (0%)	0	1/404 (0.2%)	1
SHOCK HAEMORRHAGIC	1/398 (0.3%)	1	0/404 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Crenezumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/398 (19.3%)		85/404 (21%)
Infections and infestations
NASOPHARYNGITIS	25/398 (6.3%)	32	24/404 (5.9%)	28
Injury, poisoning and procedural complications
FALL	20/398 (5%)	34	19/404 (4.7%)	26
Nervous system disorders
HEADACHE	22/398 (5.5%)	28	25/404 (6.2%)	30
Vascular disorders
HYPERTENSION	15/398 (3.8%)	18	27/404 (6.7%)	29

Limitations/Caveats

This study was discontinued due to an interim analysis in the BN29552 study, which indicated that Crenezumab was unlikely to meet its primary endpoint. No participants reached Week 105 for primary and secondary efficacy endpoints.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.