A Study of Gantenerumab in Participants With Mild Alzheimer Disease

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02051608
• Collaborator: (none)
• Enrollment: 389
• Locations: 131
• Arms: 4
• Actual Duration (Months): 84.7
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Part 1 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of gantenerumab in participants with mild Alzheimer disease. Participants will be randomized to receive either gantenerumab subcutaneously every 4 weeks or placebo subcutaneously every 4 weeks. Approved Alzheimer medication is allowed if on stable dose for 3 months prior to screening. Part 2 is an open-label extension (OLE).

A positron emission tomography (PET) imaging substudy will be conducted within the main study. Eligible participants who provide separate informed consent will undergo PET imaging scans using the radioligand florbetapir as a pharmacodynamic measure of changes in brain amyloid load over time.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 389 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Study of Gantenerumab in Patients With Mild Alzheimer's Disease; Part II: Open-Label Extension For Participating Patients
• Actual Study Start Date: Mar 27, 2014
• Actual Primary Completion Date: Apr 16, 2021
• Actual Study Completion Date: Apr 16, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Part 1 (Double Blind treatment): Placebo Participants received matching placebo by subcutaneous (SC) injection every 4 weeks (Q4W) up to 100 weeks during Part 1 of the study.	Drug: Placebo; Participants received Placebo SC injection Q4W.
Experimental: Part 1 (Double Blind treatment): Gantenerumab Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.	Drug: Gantenerumab; Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W.
Placebo Comparator: Part 2 (Open-Label Extension [OLE] treatment): Placebo switched to Gantenerumab Up to 1200 mg Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Drug: Placebo; Participants received Placebo SC injection Q4W.
Experimental: Part 2 (OLE treatment): Gantenerumab up to 1200 mg Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Drug: Gantenerumab; Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W.

Outcome Measures

Primary Outcome Measures

1. Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) [First dose up to 4 weeks after the last dose of study drug (up to 249 weeks)]

   An AE 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. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.

2. Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs) [First dose up to last dose (Baseline up to until maximum 5 years)]

   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 participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage 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 percentage 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.

3. Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment [First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks)]

   Percentage of participants with adverse events leading to discontinuation from treatment were reported.

Secondary Outcome Measures

1. Part 1: Percentage of Participants With AEs, SAEs [First dose up to last dose (Up to approximately 152 weeks)]

   An AE 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. A serious adverse event is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.

2. Part 1: Percentage of Participants With Treatment Emergent ADAs [First dose up to last dose (Up to approximately 152 weeks)]

   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 participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage 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 percentage 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.

3. Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints [Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4]

4. Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment [First dose up to last dose (Up to approximately 152 weeks)]

   Percentage of participants with adverse events leading to discontinuation from treatment were reported.

5. Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 [Baseline (Part 1 screening), Week 104]

   Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analyzed at Week 104 using magnetic resonance imaging.

6. Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104 [Baseline (Part 1 screening), Week 104]

   Change from baseline brain volume were analyzed at Week 104 using magnetic resonance imaging.

7. Part 2: Percent Change From Baseline in Cortical Thickness at Week 104 [Baseline (Part 1 screening), Week 104]

   Change from baseline in cortical thickness were analyzed at Week 104 using magnetic resonance imaging.

8. Part 2: Ventricular Volume as Measured by MRI at Week 104 [Part 2: Week 104]

   Ventricular volume were analyzed at Week 104 using magnetic resonance imaging.

9. Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints [Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101]

10. Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants [Baseline, Week 156]

    Brain amyloid load over time was assessed using a Florbetapir [F18] injection, a positron emission tomography (PET) radioligand selective to amyloid. Analysis was conducted in a subset of participants who signed consent to participate in the PET substudy. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The composite region was composed of the following six bilateral regions: frontal lobe, parietal lobe, temporal lobe, posterior cingulate cortex, anterior cingulate cortex. The reference region used to normalize the composite region was the cerebellar cortex. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans.

Other Outcome Measures

1. Part 1: Mean Change From Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104 [Baseline, Week 104]

2. Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scores at Week 104 [Baseline, Week 104]

3. Part 1: Percentage Change From Baseline in Total Tau (T-tau) in CSF at Week 104 [Baseline, Week 104]

4. Part 1: Percentage Change From Baseline in Abeta 1-42 Levels in CSF at Week 104 [Baseline, Week 104]

5. Part 1: Percentage Change From Baseline in Phosphorylated Tau [P-tau] in CSF at Week 104 [Baseline, Week 104]

6. Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104 [Baseline, Week 104]

7. Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104 [Baseline, Week 104]

8. Part 1: Percent Change From Baseline in Cortical Thickness at Week 104 [Baseline, Week 104]

9. Part 1: Ventricular Volume as Measured by MRI at Week 104 [Baseline, Week 104]

10. Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104 [Baseline, Week 104]

11. Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104 [Baseline, Week 104]

12. Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104 [Baseline, Week 104]

13. Part 1: Change From Baseline in NPI Domain Score at Week 104 [Baseline, Week 104]

14. Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104 [Baseline, Week 104]

15. Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104 [Baseline, Week 104]

16. Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104 [Baseline, Week 104]

17. Part 1: Change From Baseline in Dependence Scale (DS) at Week 104 [Baseline, Week 104]

18. Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104 [Baseline, Week 104]

19. Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104 [Baseline, Week 104]

20. Part 1: Time to Clinical Decline [Baseline up to Week 104]

21. Part 1: Change From Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104 [Baseline, Week 104]

22. Part 1: Percentage of Participants With ADAS-Cog Response [Baseline up to Week 152]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinical diagnosis of probable mild Alzheimer disease (AD) based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria or major NCD based whether or not receiving AD approved medication

• Cerebral spinal fluid (CSF) result consistent with the presence of amyloid pathology

• Availability of a person ('caregiver') who in the investigator's judgment has frequent and sufficient contact with the participant, and is able to provide accurate information regarding the participant's cognitive and functional abilities

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

• Willingness and ability to complete all aspects of the study

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

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

• Agreement not to participate in other research studies for the duration of this trial and its associated substudies

PART 2 - All participants who have been randomized and are actively participating in the study are eligible for Part 2

Exclusion Criteria:

• Dementia or neurocognitive disorder (NCD) due to a condition other than AD, including, but not limited to, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, Huntington disease, or vascular dementia

• History or presence of clinically evident vascular disease potentially affecting the brain that in the opinion of the investigator has the potential to affect cognitive function

• History or presence of stroke within the past 2 years or documented history of transient ischemic attack within the last 12 months

• History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease with associated cognitive deficits

• History of schizophrenia, schizoaffective disorder, or bipolar disorder

• Alcohol and/or substance use disorder (according to the DSM-5) within the past 2 years (nicotine use is allowed)

• History or presence of atrial fibrillation

• Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, cardiac failure New York Heart Association Class II or higher)

• Uncontrolled hypertension

• Chronic kidney disease

• Impaired hepatic function

PET imaging substudy, in addition to above:

• Prior participation in other research study or clinical care within the last year such that the total radiation exposure would exceed the local or national annual limits

Part 2 Participants who have been discontinued from the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Sun Health Research Insitute	Sun City	Arizona	United States	85351
2	Territory Neurology and Research Institute	Tucson	Arizona	United States	85704
3	ATP Clinical Research, Inc	Costa Mesa	California	United States	92626
4	Pacific Research Network - PRN	San Diego	California	United States	92103
5	California Neuroscience Research Medical Group, Inc	Sherman Oaks	California	United States	91403
6	Meridien Research	Brooksville	Florida	United States	34601
7	Brain Matters Research, Inc.	Delray Beach	Florida	United States	33445
8	Neuropsychiatric Research; Center of Southwest Florida	Fort Myers	Florida	United States	33912
9	Miami Jewish Health Systems; Clinical Research	Miami	Florida	United States	33137
10	Accelerated Enrollment Solutions	Orlando	Florida	United States	32806
11	University of South Florida	Tampa	Florida	United States	33613-4706
12	Alzheimer's Research and Treatment Center	Wellington	Florida	United States	33414
13	Indiana University	Indianapolis	Indiana	United States	46202
14	Pennington Biomedical Research Center	Baton Rouge	Louisiana	United States	70808
15	Louisiana Research Associates	New Orleans	Louisiana	United States	70114
16	Western Michigan University Homer Stryker M.D. School of Medicine Center for Clinical Research	Kalamazoo	Michigan	United States	49008
17	Millennium Psychiatric Associates, LLC	Saint Louis	Missouri	United States	63132
18	Alzheimer's Research Corporation	Manchester	New Jersey	United States	08759
19	Ocean Rheumatology	Toms River	New Jersey	United States	08775
20	Nathan Kline Institute	Orangeburg	New York	United States	10962
21	Richmond Behavioral Associates	Staten Island	New York	United States	10312
22	Alzheimer's Memory Center	Matthews	North Carolina	United States	28105
23	Richard H Weisler, MD	Raleigh	North Carolina	United States	27609
24	Central States Research	Tulsa	Oklahoma	United States	74136
25	Abington Neurological Associates	Abington	Pennsylvania	United States	19001
26	Northeastern Pennsylvania Memory	Plains	Pennsylvania	United States	18705
27	Rhode Island Mood & Memory Research Institute	East Providence	Rhode Island	United States	02914
28	Neurology Clinic PC	Cordova	Tennessee	United States	38018
29	Senior Adults Specialty Research	Austin	Texas	United States	78757
30	University of Utah, Center for Alzheimer's Care Imaging & Research	Salt Lake City	Utah	United States	84108
31	Instituto Neurologia Bs As	Ciudad Autonoma Buenos Aires		Argentina	C1426ANZ
32	Royal Adelaide Hospital; Memory Trials Centre	Adelaide	South Australia	Australia	5000
33	The Queen Elizabeth Hospital; Neurology	Woodville	South Australia	Australia	5011
34	Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre	Heidelberg West	Victoria	Australia	3081
35	Australian Alzheimer's Research Foundation	Nedlands	Western Australia	Australia	6009
36	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
37	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
38	Shat Np Sveti Naum; 3Rd Clinic of Neurology	Sofia		Bulgaria	1113
39	MBAL St. Marina; First Neurology Department	Varna		Bulgaria	9010
40	University of Calgary; Heritage Medical Research Clinic	Calgary	Alberta	Canada	T2N 4Z6
41	True North Clinical Research-Halifax	Halifax	Nova Scotia	Canada	B3S 1N2
42	True North Clinical Research	New Minas	Nova Scotia	Canada	B4N 3R7
43	Jbn Medical Diagnostic Services Inc.	Burlington	Ontario	Canada	L7M 4Y1
44	Parkwood Hospital; Geriatric Medicine	London	Ontario	Canada	N6C 5J1
45	Kawartha Centre - Redefining Healthy Aging	Peterborough	Ontario	Canada	K9H 2P4
46	Toronto Memory Program	Toronto	Ontario	Canada	M3B 2S7
47	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
48	Recherches Neuro-Hippocame	Gatineau	Quebec	Canada	J8T 8J1
49	NeuroSearch Developpements inc	Greenfield Park	Quebec	Canada	J4V 2J2
50	Jewish General Hospital / McGill University	Montreal	Quebec	Canada	H3T 1E2
51	Centre Hospitalier Affilie Universitaire de Quebec - Hopital de L'Enfant Jesus	Quebec City	Quebec	Canada	G1J 1Z4
52	McGill Univeristy; Douglas Mental Health University Institute; Neurological and Psychiatric	Verdun	Quebec	Canada	H4H 1R3
53	Alpha Recherche Clinique	Quebec		Canada	G3K 2P8
54	Aarhus Universitetshospital, Neurologisk Afdeling F, Demensklinikken	Aarhus N		Denmark	8200
55	Rigshospitalet, Hukommelsesklinikken	Koebenhavn Oe		Denmark	2100
56	University of Eastern Finland	Kuopio		Finland	70210
57	CRST Oy	Turku		Finland	20520
58	Hopital Pellegrin; Cmrr Aquitaine	Bordeaux		France	33076
59	Hopital Pierre Wertheimer; Laboratoire De Neuro Psychologie	Bron		France	69677
60	CHU de Limoges Hopital Dupuytren; Service de Medecine Geriatrique	Limoges		France	87042
61	CHU de la Timone - Hopital d Adultes; Service de Neurologie	Marseille		France	13005
62	CHU Rennes - hopital Hotel Dieu; Consultation Memoire - Gerontologie	Rennes		France	35064
63	Hopital Hautepierre; Centre dInvestigation Clinique	Strasbourg		France	67098
64	Hopital la Grave; Gerontopole - Centre de Recherche Clinique	Toulouse		France	31059
65	ECRC Experimental and Clinical Research Center, Charité Campus Berlin Buch, Memory Clinic	Berlin		Germany	13125
66	PANAKEIA - Arzneimittelforschung Leipzig GmbH	Leipzig		Germany	04275
67	Pharmakologisches Studienzentrum	Mittweida		Germany	09648
68	Klinikum rechts der Isar der TU München; Klinikapotheke	Muenchen		Germany	81675
69	Neurologische Praxis Dr. Andrej Pauls	München		Germany	80331
70	Universitätsklinikum Ulm; Klinik für Neurologie	Ulm		Germany	89081
71	Studienzentrum Nordwest, Dr. med. Joachim Springub / Herr Wolfgang Schwarz	Westerstede		Germany	26655
72	Semmelweis University; Department of Neurology	Budapest		Hungary	1083
73	Nuovo Ospedale Civile S. Agostino-Estense; Clinica Neurologica - Dipartimento di Neuroscienze	Modena	Emilia-Romagna	Italy	41126
74	Azienda Ospedaliera Universitaria Policlinico Tor Vergata; Neurologia	Roma	Lazio	Italy	00133
75	Umberto I Policlinico di Roma-Università di Roma La Sapienza	Roma	Lazio	Italy	00185
76	IRCCS "Centro S. Giovanni di Dio" Fatebenefratelli -UO Alzheimer	Brescia	Lombardia	Italy	25125
77	Irccs Multimedica Santa Maria; Unita' Di Neurologia	Castellanza	Lombardia	Italy	21053
78	ASST DI MONZA; Neurologia	Monza	Lombardia	Italy	20900
79	A.O. Universitaria Pisana; Neurologia	Pisa	Toscana	Italy	56126
80	Medical Corporation Hakuyokai Kashiwado Hospital	Chiba		Japan	260-8656
81	National Hospital Organization Chiba-east Hospital; Neurology	Chiba		Japan	260-8712
82	Juntendo University Urayasu Hospital; Neurology	Chiba		Japan	279-0021
83	Fukuoka University Hospital; Neurology and Health Care	Fukuoka		Japan	814-0180
84	Maebashi Red Cross Hospital; Neurology	Gunma		Japan	371-0014
85	National Hospital Organization Hiroshima-Nishi Medical Center	Hiroshima		Japan	739-0696
86	Hyogo Brain and Heart Center at Himeji; Department of Aging Brain and Cognitive Disorders	Hyogo		Japan	670-0981
87	Shonan Kamakura General Hospital; Neurology	Kanagawa		Japan	247-8533
88	Oita University Hospital; Neurology	Oita		Japan	879-5593
89	Kurashiki Heisei Hospital; Neurology	Okayama		Japan	710-0826
90	Shizuoka City Shimizu Hospital; Neurology	Shizuoka		Japan	424-0911
91	Dong-A University Medical Center	Busan		Korea, Republic of	602-715
92	Seoul National University Bundang Hospital; Neurology Department	Gyeonggi-do		Korea, Republic of	13620
93	Inha University Hospital; Neurology Department	Incheon		Korea, Republic of	22332
94	Konkuk University Medical Center	Seoul		Korea, Republic of	05030
95	Samsung Medical Center	Seoul		Korea, Republic of	06351
96	Ewha Womans University Hospital (Seoul)	Seoul		Korea, Republic of	07804
97	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	137-701
98	Asan Medical Center.	Seoul		Korea, Republic of	138-736
99	Ewha Womans University Mokdong Hospital; Dept of Neurology	Seoul		Korea, Republic of	158-710
100	Brain Research Center B.V	Amsterdam		Netherlands	1081 GN
101	Erasmus Mc - Locatie Centrum; Dept of Neurology	Rotterdam		Netherlands	3015 GD
102	Hospital Prof. Dr. Fernando Fonseca; Servico de Neurologia	Amadora		Portugal	2720-276
103	Hospital de Santa Maria; Servico de Neurologia	Lisboa		Portugal	1649-035
104	State Autonomous Healthcare Institution "Republican Clinical Neurological Center	Kazan		Russian Federation	420021
105	State autonomous institution of healthcare Inter-regional clinical and diagnostic center	Kazan		Russian Federation	420101
106	Institution of RAMS (Mental Health Research Center of RAMS)	Moscow		Russian Federation	115522
107	SBEI of HPI The 1st Moscow State Medical University n.a. I.M. Sechenov of MOH of RF	Moscow		Russian Federation	119021
108	Saint Petersburg State Institution of Healthcare City Geriatric Medico-Social Center	Saint Petersburg		Russian Federation	190103
109	City Clinical Hospital # 2 n.a. V.I. Razumovsky	Saratov		Russian Federation	410028
110	Russian Medical Military Academy n.a. S.M.Kirov; Neurology Department	St. Petersburg		Russian Federation	194044
111	Hospital General Universitario de Elche; Servicio de Neurología	Elche	Alicante	Spain	03203
112	Fundació ACE	BArcelon	Barcelona	Spain	08034
113	Policlínica Guipuzkoa; Servicio de Neurología	Donosti-San Sebastián	Guipuzcoa	Spain	20014
114	Hospital de Cruces; Servicio de Neurologia	Barakaldo	Vizcaya	Spain	48903
115	Hospital del Mar; Servicio de Neurologia	Barcelona		Spain	08003
116	Hospital Universitario 12 de Octubre; Servicio de Neurologia	Madrid		Spain	28041
117	Hospital Universitario Virgen Macarena; Servicio de Neurologia	Sevilla		Spain	41009
118	Hospital Universitari i Politecnic La Fe	Valencia		Spain	46026
119	Skånes Universitetssjukhus Malmö, Minneskliniken	Malmö		Sweden	211 46
120	KAROLINSKA UNI HOSPITAL, HUDDINGE; Mottagning Kognitiv Forskning, M54	Stockholm		Sweden	141 86
121	Felix Platter-Spital Medizin Geriatrie	Basel		Switzerland	4002
122	CHUV Lausanne Memory clinique	Lausanne		Switzerland	1011
123	Istanbul University Istanbul School of Medicine; Neurology	Istanbul		Turkey	34093
124	Dokuz Eylul University Medicine Faculty; Noroloji Departmani	Izmir		Turkey	35340
125	Ondokuz Mayis University School of Medicine; Neurology	Samsun		Turkey	55139
126	Sussex Partnership NHS Foundation Trust; Cognitive Treatment and Research unit	Crowborough		United Kingdom	TN6 1HB
127	Glasgow Memory Clinic	Glasgow		United Kingdom	G20 0XA
128	Charing Cross Hospital; Dept of Neurosciences	London		United Kingdom	W6 8RF
129	Manchester Royal Infirmary	Manchester		United Kingdom	M13 9WL
130	Royal Preston Hosptial	Preston		United Kingdom	PR2 9HT
131	Memory Service North	Sheffield		United Kingdom	S35 8QS

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Feb 28, 2020
• Statistical Analysis Plan - May 31, 2021

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02051608
• Other Study ID Numbers: WN28745; 2013-003390-95
• First Posted: Jan 31, 2014
• Last Update Posted: Jun 16, 2022
• Last Verified: May 1, 2022

• 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	Part 1 of the study was conducted at 116 centers in 21 countries and part 2 was conducted at 75 centers in 17 countries.
Pre-assignment Detail	A total of 389 participants were enrolled out of which 387 were randomized and treated (192 received gantenerumab and 195 received placebo) in part 1 of the study. Of these, a total of 230 participants enrolled into Part 2 of the study: 225 participants received at least one dose of study drug. Participants who had discontinued from Part 1 of the study were not allowed to enroll in Part 2.

Arm/Group Title	Part 1: Placebo	Part 1: Gantenerumab	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants received matching placebo by subcutaneous (SC) injection every 4 weeks (Q4W) up to 100 weeks during Part 1 of study.	Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Period Title: Part 1: Double Blind Treatment
STARTED	195	192	0	0
COMPLETED	134	136	0	0
NOT COMPLETED	61	56	0	0
Period Title: Part 1: Double Blind Treatment
STARTED	0	0	119	111
COMPLETED	0	0	49	50
NOT COMPLETED	0	0	70	61

Baseline Characteristics

Arm/Group Title	Part 1: Placebo	Part 1: Gantenerumab	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg	Total
Arm/Group Description	Participants received matching placebo by SC injection every 4 weeks Q4W up to 100 weeks during Part 1 of study.	Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Total of all reporting groups
Overall Participants	195	192	117	108	612
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.1 (8.6)	69.7 (8.9)	69.9 (8.7)
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.82 (8.09)	71.01 (9.31)	71.43 (8.69)
Sex: Female, Male (Count of Participants)
Female	113 57.9%	98 51%	211 180.3%
Male	82 42.1%	94 49%	176 150.4%
Sex: Female, Male (Count of Participants)
Female	69 35.4%	61 31.8%	130 111.1%
Male	48 24.6%	47 24.5%	95 81.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 5.6%	12 6.3%	23 19.7%
Not Hispanic or Latino	178 91.3%	176 91.7%	354 302.6%
Unknown or Not Reported	6 3.1%	4 2.1%	10 8.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 4.6%	10 5.2%	19 16.2%
Not Hispanic or Latino	108 55.4%	96 50%	204 174.4%
Unknown or Not Reported	0 0%	2 1%	2 1.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	23 11.8%	21 10.9%	44 37.6%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.5%	1 0.9%
Black or African American	2 1%	2 1%	4 3.4%
White	164 84.1%	166 86.5%	330 282.1%
More than one race	1 0.5%	0 0%	1 0.9%
Unknown or Not Reported	5 2.6%	2 1%	7 6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	19 9.7%	19 9.9%	38 32.5%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.5%	1 0.9%
Black or African American	2 1%	2 1%	4 3.4%
White	94 48.2%	85 44.3%	179 153%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1%	1 0.5%	3 2.6%

Outcome Measures

1. Primary Outcome

Title	Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
Description	An AE 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. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.
Time Frame	First dose up to 4 weeks after the last dose of study drug (up to 249 weeks)

Outcome Measure Data

Analysis Population Description

The safety-evaluable population consisted of all participants who had received at least one dose of study drug, regardless of whether the participant withdrew prematurely or not.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	117	108
AEs	91.5 46.9%	95.4 49.7%
SAEs	24.8 12.7%	38.0 19.8%

2. Primary Outcome

Title	Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs)
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 participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage 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 percentage 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	First dose up to last dose (Baseline up to until maximum 5 years)

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	115	106
Number [Percentage of Participants]	2.6 1.3%	2.8 1.5%

3. Primary Outcome

Title	Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment
Description	Percentage of participants with adverse events leading to discontinuation from treatment were reported.
Time Frame	First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks)

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	117	108
Number [Percentage of Participants]	12.0 6.2%	15.7 8.2%

4. Secondary Outcome

Title	Part 1: Percentage of Participants With AEs, SAEs
Description	An AE 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. A serious adverse event is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.
Time Frame	First dose up to last dose (Up to approximately 152 weeks)

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.

Arm/Group Title	Part 1: Placebo	Part 1: Gantenerumab
Arm/Group Description	Participants received matching placebo by SC injection every 4 weeks Q4W up to 100 weeks during Part 1 of study.	Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
Measure Participants	195	192
AEs	80.5 41.3%	82.8 43.1%
SAEs	12.3 6.3%	12.0 6.3%

5. Secondary Outcome

Title	Part 1: Percentage of Participants With Treatment Emergent ADAs
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 participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage 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 percentage 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	First dose up to last dose (Up to approximately 152 weeks)

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.

Arm/Group Title	Part 1: Placebo	Part 1: Gantenerumab
Arm/Group Description	Participants received matching placebo by SC injection every 4 weeks Q4W up to 100 weeks during Part 1 of study.	Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
Measure Participants	194	191
Number [Percentage of Participants]	3.6 1.8%	11.5 6%

6. Secondary Outcome

Title	Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints
Time Frame	Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) evaluable population consisted of all participants that were treated with gantenerumab and provided at least 1 post-baseline PK sample. Number analyzed is the number of participants with data available for analyses at the given time-point.

Arm/Group Title	Gantenerumab
Arm/Group Description	Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
Measure Participants	192
Day 4	4.11 (2.59)
Week 4	2.06 (0.89)
Week 8	3.11 (1.41)
Week 12	3.35 (1.63)
Week 24	3.71 (2.13)
Week 48	7.61 (3.88)
Week 72	7.66 (4.44)

7. Secondary Outcome

Title	Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment
Description	Percentage of participants with adverse events leading to discontinuation from treatment were reported.
Time Frame	First dose up to last dose (Up to approximately 152 weeks)

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not.

Arm/Group Title	Part 1: Placebo	Part 1: Gantenerumab
Arm/Group Description	Participants received matching placebo by SC injection every 4 weeks Q4W up to 100 weeks during Part 1 of study.	Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
Measure Participants	195	192
Number [Percentage of Participants]	2.6 1.3%	6.8 3.5%

8. Other Pre-specified Outcome

Title	Part 1: Mean Change From Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scores at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Part 1: Percentage Change From Baseline in Total Tau (T-tau) in CSF at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Part 1: Percentage Change From Baseline in Abeta 1-42 Levels in CSF at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Part 1: Percentage Change From Baseline in Phosphorylated Tau [P-tau] in CSF at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Part 1: Percent Change From Baseline in Cortical Thickness at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Part 1: Ventricular Volume as Measured by MRI at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in NPI Domain Score at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

21. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

22. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

23. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

24. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Dependence Scale (DS) at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

25. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

26. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

27. Other Pre-specified Outcome

Title	Part 1: Time to Clinical Decline
Time Frame	Baseline up to Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

28. Other Pre-specified Outcome

Title	Part 1: Change From Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

29. Other Pre-specified Outcome

Title	Part 1: Percentage of Participants With ADAS-Cog Response
Time Frame	Baseline up to Week 152

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

30. Secondary Outcome

Title	Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104
Description	Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analyzed at Week 104 using magnetic resonance imaging.
Time Frame	Baseline (Part 1 screening), Week 104

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure. Number analyzed is the number of participants with data available for analyses at the given time-point.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab by SC injection in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	52	44
Hippocampal Left Volume- Percent Change at Week 104	-11.24 (4.04)	-12.10 (4.45)
Hippocampal Right Volume- Percent Change at Week 104	-12.49 (4.03)	-11.34 (4.41)

31. Secondary Outcome

Title	Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104
Description	Change from baseline brain volume were analyzed at Week 104 using magnetic resonance imaging.
Time Frame	Baseline (Part 1 screening), Week 104

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab by SC injection in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	54	44
Mean (Standard Deviation) [Percent Change]	-4.89 (1.90)	-4.91 (1.58)

32. Secondary Outcome

Title	Part 2: Percent Change From Baseline in Cortical Thickness at Week 104
Description	Change from baseline in cortical thickness were analyzed at Week 104 using magnetic resonance imaging.
Time Frame	Baseline (Part 1 screening), Week 104

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab by SC injection in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	54	44
Mean (Standard Deviation) [Percent Change]	-5.84 (2.33)	-5.58 (1.87)

33. Secondary Outcome

Title	Part 2: Ventricular Volume as Measured by MRI at Week 104
Description	Ventricular volume were analyzed at Week 104 using magnetic resonance imaging.
Time Frame	Part 2: Week 104

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of gantenerumab during the OLE and also had at least one post baseline MRI. The number of participants analyzed indicates the number of participants evaluated for the outcome measure.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab by SC injection in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	63	52
Mean (Standard Deviation) [mL]	86.70 (38.37)	86.21 (30.49)

34. Secondary Outcome

Title	Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints
Time Frame	Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101

Outcome Measure Data

Analysis Population Description

Of the 225 participants in the OLE safety evaluable population, evaluable PK information was available from 223 participants. The PK evaluable population consisted of all participants that were treated with gantenerumab and provided at least 1 post-baseline PK sample. Number analysed is the number of participants with data available for analyses at the given time-point.

Arm/Group Title	Part 2 (OLE Treatment): Gantenerumab 1200 mg
Arm/Group Description	Participants who had received placebo or gantenerumab in Part 1, received gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	223
Week 53	80.6 (38.4)
Week 101	89.1 (33.6)
Week 104	43.5 (22.4)
Week 116	3.66 (2.29)
Week 156	45.2 (22.5)
Week 208	55.8 (37.9)

35. Secondary Outcome

Title	Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants
Description	Brain amyloid load over time was assessed using a Florbetapir [F18] injection, a positron emission tomography (PET) radioligand selective to amyloid. Analysis was conducted in a subset of participants who signed consent to participate in the PET substudy. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The composite region was composed of the following six bilateral regions: frontal lobe, parietal lobe, temporal lobe, posterior cingulate cortex, anterior cingulate cortex. The reference region used to normalize the composite region was the cerebellar cortex. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans.
Time Frame	Baseline, Week 156

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who had received at least one dose of study drug, regardless of whether the participants withdrew prematurely or not. The number of participants analysed indicates the number of participants evaluated for the outcome measure.

Arm/Group Title	Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg	Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.	Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
Measure Participants	13	8
Mean (Standard Deviation) [Score on a scale]	-81.01 (47.08)	-84.93 (28.38)

Adverse Events

Time Frame	Baseline up to 52 weeks after the last dose of study drug (up to 7 years)
Adverse Event Reporting Description	The safety-evaluable population consisted of all participants who had received at least one dose of study drug, regardless of whether the participant withdrew prematurely or not.
Arm/Group Title	Part 1: Placebo		Part 1: Gantenerumab		Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg		Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
Arm/Group Description	Participants received matching placebo by SC injection every 4 weeks Q4W up to 100 weeks during Part 1 of study.		Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.		Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.		Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
All Cause Mortality
	Part 1: Placebo		Part 1: Gantenerumab		Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg		Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/195 (5.6%)		8/192 (4.2%)		5/117 (4.3%)		5/108 (4.6%)
Serious Adverse Events
	Part 1: Placebo		Part 1: Gantenerumab		Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg		Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/195 (27.2%)		61/192 (31.8%)		29/117 (24.8%)		41/108 (38%)
Cardiac disorders
Acute coronary syndrome	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Acute myocardial infarction	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Angina unstable	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Arrhythmia	0/195 (0%)	0	3/192 (1.6%)	3	0/117 (0%)	0	2/108 (1.9%)	2
Atrial fibrillation	1/195 (0.5%)	1	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Bradycardia	1/195 (0.5%)	1	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Cardiac arrest	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Cardiac failure	1/195 (0.5%)	1	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Cardiac failure acute	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Myocardial infarction	2/195 (1%)	2	1/192 (0.5%)	1	1/117 (0.9%)	1	1/108 (0.9%)	1
Eye disorders
Ocular hypertension	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Gastrointestinal disorders
Constipation	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Diverticulum intestinal haemorrhagic	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Dysphagia	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Enteritis	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Faeces discoloured	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Gastric ulcer	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Gastrointestinal haemorrhage	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Haematochezia	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Ileus	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Inguinal hernia	0/195 (0%)	0	2/192 (1%)	2	0/117 (0%)	0	2/108 (1.9%)	2
Lower gastrointestinal haemorrhage	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Pancreatitis	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Umbilical hernia	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
General disorders
Asthenia	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Cyst	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Death	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Fatigue	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Pain	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Liver disorder	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Immune system disorders
Anaphylactic shock	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Infections and infestations
Appendiceal abscess	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Bacterial sepsis	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
COVID-19	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Cellulitis	0/195 (0%)	0	2/192 (1%)	2	0/117 (0%)	0	2/108 (1.9%)	2
Colonic abscess	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Cystitis	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Erysipelas	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Gastroenteritis rotavirus	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Influenza	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Periodontitis	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Pneumonia	3/195 (1.5%)	3	1/192 (0.5%)	1	2/117 (1.7%)	2	1/108 (0.9%)	1
Respiratory tract infection	3/195 (1.5%)	3	0/192 (0%)	0	3/117 (2.6%)	3	0/108 (0%)	0
Sepsis	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Septic shock	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Shunt infection	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Tonsillitis bacterial	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Urinary tract infection	3/195 (1.5%)	3	3/192 (1.6%)	3	3/117 (2.6%)	3	2/108 (1.9%)	2
Injury, poisoning and procedural complications
Ankle fracture	1/195 (0.5%)	2	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Chest injury	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Comminuted fracture	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Fall	3/195 (1.5%)	3	5/192 (2.6%)	5	0/117 (0%)	0	3/108 (2.8%)	3
Femoral neck fracture	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Femur fracture	1/195 (0.5%)	1	2/192 (1%)	2	1/117 (0.9%)	1	1/108 (0.9%)	1
Hip fracture	1/195 (0.5%)	1	1/192 (0.5%)	1	1/117 (0.9%)	1	1/108 (0.9%)	1
Jaw fracture	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Meniscus injury	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Multiple fractures	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Optic nerve injury	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Rib fracture	2/195 (1%)	2	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Road traffic accident	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Spinal compression fracture	0/195 (0%)	0	2/192 (1%)	2	0/117 (0%)	0	2/108 (1.9%)	2
Subdural haematoma	2/195 (1%)	2	2/192 (1%)	2	1/117 (0.9%)	1	2/108 (1.9%)	2
Traumatic intracranial haemorrhage	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Upper limb fracture	1/195 (0.5%)	1	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Wrist fracture	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Investigations
Electrocardiogram abnormal	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Hypercalcaemia	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Hypoglycaemia	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Hyponatraemia	0/195 (0%)	0	2/192 (1%)	2	0/117 (0%)	0	1/108 (0.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma	1/195 (0.5%)	1	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Cerebellar tumour	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Colon cancer	2/195 (1%)	2	0/192 (0%)	0	2/117 (1.7%)	2	0/108 (0%)	0
Invasive lobular breast carcinoma	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Myelodysplastic syndrome	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Ovarian epithelial cancer	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Rectal cancer	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Squamous cell carcinoma of pharynx	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Nervous system disorders
ARIA-E	2/195 (1%)	2	2/192 (1%)	3	2/117 (1.7%)	2	2/108 (1.9%)	2
ARIA-H	0/195 (0%)	0	2/192 (1%)	2	0/117 (0%)	0	1/108 (0.9%)	1
Brain stem infarction	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Cerebral haematoma	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Cerebral infarction	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Cerebral venous sinus thrombosis	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Cerebrovascular accident	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Dementia Alzheimer's type	2/195 (1%)	2	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Dementia of the Alzheimer's type, with delusions	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Encephalopathy	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Epilepsy	1/195 (0.5%)	1	2/192 (1%)	2	1/117 (0.9%)	1	1/108 (0.9%)	1
Generalised tonic-clonic seizure	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Haemorrhagic stroke	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Hemiplegia	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Hydrocephalus	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Ischaemic stroke	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Leukoencephalopathy	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Nervous system disorder	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Neurotoxicity	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Psychomotor hyperactivity	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Somnolence	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Syncope	2/195 (1%)	2	2/192 (1%)	2	1/117 (0.9%)	1	2/108 (1.9%)	2
Transient ischaemic attack	2/195 (1%)	2	0/192 (0%)	0	2/117 (1.7%)	2	0/108 (0%)	0
Vertebral artery dissection	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Vertebrobasilar stroke	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Psychiatric disorders
Affective disorder	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Aggression	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Agitation	1/195 (0.5%)	1	1/192 (0.5%)	2	0/117 (0%)	0	1/108 (0.9%)	2
Delirium	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Psychotic symptom	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Suicide threat	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Renal and urinary disorders
Haematuria	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Urinary retention	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Urinary tract obstruction	0/195 (0%)	0	2/192 (1%)	2	0/117 (0%)	0	2/108 (1.9%)	2
Respiratory, thoracic and mediastinal disorders
Bronchitis chronic	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Epistaxis	1/195 (0.5%)	2	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Lung infiltration	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Pleural effusion	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Pneumonia aspiration	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Pulmonary embolism	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Tonsillar hypertrophy	1/195 (0.5%)	1	0/192 (0%)	0	0/117 (0%)	0	0/108 (0%)	0
Vascular disorders
Aortic aneurysm rupture	1/195 (0.5%)	1	0/192 (0%)	0	1/117 (0.9%)	1	0/108 (0%)	0
Deep vein thrombosis	1/195 (0.5%)	1	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Giant cell arteritis	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Hypertension	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	0/108 (0%)	0
Orthostatic hypotension	0/195 (0%)	0	1/192 (0.5%)	1	0/117 (0%)	0	1/108 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Part 1: Placebo		Part 1: Gantenerumab		Part 2 (OLE Treatment): Placebo Switched to Gantenerumab up to 1200 mg		Part 2 (OLE Treatment): Gantenerumab up to 1200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	147/195 (75.4%)		159/192 (82.8%)		94/117 (80.3%)		91/108 (84.3%)
Gastrointestinal disorders
Constipation	14/195 (7.2%)	15	16/192 (8.3%)	20	6/117 (5.1%)	7	12/108 (11.1%)	15
Diarrhoea	23/195 (11.8%)	27	11/192 (5.7%)	18	11/117 (9.4%)	14	8/108 (7.4%)	13
Nausea	15/195 (7.7%)	24	10/192 (5.2%)	11	3/117 (2.6%)	9	4/108 (3.7%)	4
Vomiting	11/195 (5.6%)	16	14/192 (7.3%)	18	6/117 (5.1%)	11	6/108 (5.6%)	7
General disorders
Injection site reaction	49/195 (25.1%)	284	52/192 (27.1%)	322	48/117 (41%)	281	44/108 (40.7%)	280
Oedema peripheral	2/195 (1%)	2	10/192 (5.2%)	11	1/117 (0.9%)	1	8/108 (7.4%)	9
Pyrexia	4/195 (2.1%)	4	7/192 (3.6%)	9	2/117 (1.7%)	2	6/108 (5.6%)	8
Infections and infestations
Bronchitis	10/195 (5.1%)	13	10/192 (5.2%)	11	6/117 (5.1%)	9	5/108 (4.6%)	6
Influenza	8/195 (4.1%)	10	14/192 (7.3%)	19	4/117 (3.4%)	4	10/108 (9.3%)	12
Nasopharyngitis	27/195 (13.8%)	35	23/192 (12%)	31	13/117 (11.1%)	14	11/108 (10.2%)	15
Upper respiratory tract infection	20/195 (10.3%)	30	7/192 (3.6%)	12	10/117 (8.5%)	13	3/108 (2.8%)	5
Urinary tract infection	17/195 (8.7%)	20	18/192 (9.4%)	28	11/117 (9.4%)	13	7/108 (6.5%)	14
Injury, poisoning and procedural complications
Contusion	12/195 (6.2%)	15	16/192 (8.3%)	21	5/117 (4.3%)	7	8/108 (7.4%)	9
Fall	28/195 (14.4%)	44	35/192 (18.2%)	69	16/117 (13.7%)	25	22/108 (20.4%)	41
Skin abrasion	6/195 (3.1%)	7	12/192 (6.3%)	17	3/117 (2.6%)	3	5/108 (4.6%)	10
Musculoskeletal and connective tissue disorders
Arthralgia	14/195 (7.2%)	15	13/192 (6.8%)	23	8/117 (6.8%)	8	7/108 (6.5%)	10
Back pain	20/195 (10.3%)	21	17/192 (8.9%)	19	8/117 (6.8%)	9	5/108 (4.6%)	5
Neck pain	6/195 (3.1%)	6	2/192 (1%)	2	6/117 (5.1%)	6	1/108 (0.9%)	1
Nervous system disorders
ARIA-E	32/195 (16.4%)	42	42/192 (21.9%)	70	29/117 (24.8%)	35	30/108 (27.8%)	51
ARIA-H	30/195 (15.4%)	39	36/192 (18.8%)	42	19/117 (16.2%)	23	23/108 (21.3%)	27
Dizziness	18/195 (9.2%)	24	17/192 (8.9%)	26	13/117 (11.1%)	13	6/108 (5.6%)	6
Headache	29/195 (14.9%)	38	22/192 (11.5%)	44	15/117 (12.8%)	18	12/108 (11.1%)	24
Psychiatric disorders
Agitation	13/195 (6.7%)	16	18/192 (9.4%)	21	9/117 (7.7%)	10	8/108 (7.4%)	9
Anxiety	13/195 (6.7%)	13	13/192 (6.8%)	14	5/117 (4.3%)	5	6/108 (5.6%)	6
Depression	17/195 (8.7%)	17	13/192 (6.8%)	14	8/117 (6.8%)	8	2/108 (1.9%)	2
Insomnia	12/195 (6.2%)	15	15/192 (7.8%)	16	7/117 (6%)	8	5/108 (4.6%)	5
Skin and subcutaneous tissue disorders
Rash	9/195 (4.6%)	9	12/192 (6.3%)	12	4/117 (3.4%)	4	5/108 (4.6%)	5
Vascular disorders
Hypertension	13/195 (6.7%)	13	13/192 (6.8%)	15	4/117 (3.4%)	4	5/108 (4.6%)	5

Limitations/Caveats

As the participants transitioned early to OLE, most participants did not reach the primary analysis timepoint (Week 104). Hence, the efficacy endpoints for Part 1 became exploratory in nature.

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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.