Long-Term Safety of Gantenerumab in Participants with Alzheimer’s Disease: A Phase III, Double-Blind, and Open-Label Extension Study (Marguerite RoAD)

Background: Gantenerumab is an anti-amyloid-β immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in Marguerite RoAD (MR; NCT02051608), a Phase III, double-blind (DB), placebo-controlled study in participants with mild Alzheimer’s disease (AD) dementia. Following a preplanned futility analysis of the SCarlet RoAD study (NCT01224106), MR was converted into an open-label extension (OLE). Objective: The DB study aimed to assess the efficacy of gantenerumab compared with placebo from baseline to Week 104 in participants with mild AD dementia. Following conversion to an OLE, this objective became exploratory, as the OLE assessed the long-term safety and tolerability of SC gantenerumab at doses of up to 1,200 mg every 4 weeks (Q4W) in OLE participants. Methods: Eligible DB study participants were offered the opportunity to receive gantenerumab up-titrated to 1,200 mg Q4W. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring. Results: Overall, 225 participants were rolled over from the DB part of MR and received ≥1 gantenerumab dose in the OLE. The median treatment duration was 123 weeks. Fifty-nine (26.2%) and 41 (18.2%) participants had amyloid-related imaging abnormality (ARIA)-edema and ARIA-hemorrhage MRI findings, respectively. ARIA findings were manageable with MRI monitoring and dose intervention; most were asymptomatic. There were no unexpected safety findings. Conclusions: SC gantenerumab at doses of up to 1,200 mg Q4W were well tolerated in participants with mild AD dementia.


Outcome measures in the double-blind part
The primary objective in the double-blind part was to evaluate the efficacy of gantenerumab given at doses of 105 or 225 mg subcutaneously (SC) every 4 weeks (Q4W) from baseline to Week 104, as measured by two co-primary endpoints: cognition As the recruitment was halted and the study was converted to an open-label extension (OLE), all efficacy objectives, including the co-primary and secondary endpoints, became exploratory, given the reduced number of participants in the study and the fact that there were few participants who had completed the double-blind treatment period.
Additional secondary outcomes included the change from baseline to Week 104 in disease pathology biomarkers, assessed using cerebrospinal fluid (CSF) amyloid-β (Aβ)42, total tau (t-tau) and phosphorylated tau (p-tau).Behavior was assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q).
Safety and tolerability were assessed by magnetic resonance imaging (MRI), physical and neurologic examinations, vital signs, blood safety tests, electrocardiograms, Columbia Suicide Severity Rating Scale and adverse event (AE) monitoring.

Management of MRI findings in the double-blind part
In the case of a single amyloid-related imaging abnormalities (ARIA)-edema (ARIA-E) >2 cm or multiple ARIA-E, dosing was stopped until the ARIA-E had resolved or significantly decreased or stabilized.For single cases of ARIA-E ≤2 cm, no change of dosing was required.For participants on 225 mg gantenerumab who developed two new microhemorrhage on a single scan or 3-4 new microbleeds cumulatively, the dose was reduced to 105 mg.Participants who developed five or more new microbleeds cumulatively were discontinued from the study treatment.

Statistical analyses in the double-blind part
As a result of the recruitment being halted and the study being converted to an OLE, exploratory and descriptive statistics were applied to all endpoints in the double-blind part of the study.For participants who did not transition into the OLE, this included all data from all visits up to and including the final follow-up visit (Week 152).For participants who transitioned into the OLE, data from all visits up to and including the Week 104/early termination visit (Follow-up 1), or the last visit prior to first OLE dose, were included.No data from the OLE were used.Time windowing was used to ensure that data from all Week 104/ early termination visits were summarized at the correct timepoint.

Study population in the double-blind part
By November 2015, when recruitment for Marguerite RoAD (MR) had been suspended, a total of 389 participants had enrolled in the double-blind part of the study, of whom, 387 were treated.The disposition of participants in the double-blind and OLE parts is available in Fig. 3. Overall, 195 participants received placebo and 192 received gantenerumab.Sixtyone participants (31.3%) receiving placebo and 56 participants (29.2%) receiving gantenerumab withdrew from the study before the OLE.The most common reason for discontinuation was participant withdrawal (placebo: 21.5%; gantenerumab: 15.1%).Study withdrawals due to AEs occurred in 1.0% of those on placebo and 4.2% of those on gantenerumab.

months).
Twenty-two participants (13 participants on placebo and nine participants on gantenerumab) completed double-blind treatment in the study.

Concomitant medications in the double-blind part and OLE
In the double-blind part of the study, 15 (2.1%) participants reported use of memantine; 40 (10.3%)participants reported the use of cholinesterase inhibitors (rivastigmine, donepezil, galantine).After OLE baseline, seven (3.1%) participants reported use of memantine, five (2.2%) participants reported use of acetylcholinesterase inhibitors (donepezil or galantamine) and one (0.4%) reported the use of combination (memantine and donepezil).

Summary of AEs in the double-blind part
In the double-blind part, the mean (SD) treatment duration for participants who received gantenerumab was 65.44 (25.60) weeks.Among participants who received placebo, the mean treatment duration was 66.72 (26.58) weeks.Most participants in each treatment group experienced at least one AE (80.5% of participants on placebo and 82.8% on gantenerumab).The most common (>7%) AEs were fall (7.7% on placebo, 9.4% on gantenerumab), nasopharyngitis (7.7% on placebo, 7.3% on gantenerumab) and headache (7.7% on placebo, 6.3% on gantenerumab).Thirteen participants (6.8%) who received gantenerumab and five participants (2.6%) who received placebo had AEs that led to withdrawal from the study treatment.Nineteen participants (9.9%) on gantenerumab and 11 participants (5.6%) on placebo had AEs leading to dose modification of study treatment.
Twenty-three participants (12.0%) on gantenerumab and 24 participants (12.3%) on placebo reported serious AEs.The most frequent (>0.5%) serious AEs were fall (1.3%, five participants [1.5% on placebo and 1.0% on gantenerumab]) and atrial fibrillation (0.5%, two participants [0.5% on placebo and 0.5% on gantenerumab]).There were three deaths in the gantenerumab group (cardiac arrhythmia, cardiac arrest and fall) and three deaths in the placebo group (cardiac failure, ovarian epithelial cancer and cerebrovascular accident); all were considered unrelated to study treatment by the study investigator.There were no AEs of special interest reported (drug-induced liver injury, suspected transmission of infectious agent) and no clinically significant safety findings related to physical exams, vital signs, laboratory test results or electrocardiogram data.

Incidence of ARIA MRI findings in the double-blind part
In the double-blind part, the incidence of ARIA-E AEs was higher in those who received gantenerumab (9.4% [18 participants]) than in those who received placebo (1.5% [three participants]).The incidence of ARIA-hemorrhage (ARIA-H) AEs was 6.3% (12 participants) in those who received gantenerumab and 4.1% (eight participants) in those who received placebo.

Symptoms that were associated with ARIA-E MRI findings in the double-blind part and OLE
In the double-blind part, participants were asked up to 1 week before each MRI was performed if they had experienced central nervous system (CNS) AEs.This approach identified two AEs (irritability and headache) that were considered symptoms of ARIA-E and were temporally associated with an ARIA-E.Irritability experienced in one participant was assessed by investigator to be not related to the study treatment (placebo), whereas the headache was assessed as related to the study treatment (gantenerumab).
In the OLE, two approaches to identifying symptoms associated with ARIA-E were used.
The first was a protocol-defined approach, which is described in the main manuscript.The second approach was a post hoc analysis, whereby AEs associated with ARIA-E MRI findings were retrieved programmatically.These were defined as AEs of nervous system disorders or psychiatric disorders that had an onset within 4 weeks prior to ARIA-E onset, through to the ARIA-E resolution date.AEs of ARIA MRI findings were excluded from this analysis.Based on this approach, of the 219 participants who received gantenerumab and had a post-baseline MRI, 22 (10.0%)participants reported at least one CNS AE that was temporally associated with an ARIA-E MRI finding; a total of 33 CNS AEs were reported, the most common of which were headache (1.8%), dizziness (1.4%) and syncope (1.4%) (Supplementary Table 5).CNS symptoms associated with ARIA-E MRI findings were mostly mild to moderate in intensity; five required permanent discontinuation of study treatment (cognitive disorder, confused state, generalised tonic-clonic seizure, white matter lesion and hemiplegia).Three CNS AEs were reported as serious (two seizures and one hemiplegia); two of these three serious AEs were considered related to study treatment.

Cognition and function
In the double-blind part, treatment with gantenerumab did not lead to a statistically significant difference compared with placebo in change from baseline to Week 104 in ADAS-Cog 13 scores (mean difference: −3.71 [95% confidence interval [Cl]: −7.54, 0.12]; p=0.058) or ADCS-ADL (mean difference: 3.84 [95% Cl: −1.29, 8.97]; p=0.140); however, as the recruitment was halted and the study was converted to OLE, all efficacy objectives became exploratory.Additional efficacy data for both the double-blind and OLE stages can be found in Supplementary Table 6, Supplementary Table 7, and Supplementary Table 8.

Assessment of changes in amyloid load over time in the double-blind part
A total of 112 participants (61 on placebo and 51 on gantenerumab) had a baseline PET scan in the double-blind phase of the study.No significant change in amyloid load was observed with treatment with gantenerumab compared with placebo; however, numeric decreases in cortical composite standardized uptake value ratios (SUVRs) (reference region: cerebellum gray) were observed in those treated with gantenerumab compared with placebo at Weeks 48 and 104.

Pharmacokinetics (PK)
In the OLE, a total of 1,453 (five prior to first OLE dosing, 1,448 following first dosing) gantenerumab plasma concentration samples from 223 participants were collected over a treatment period of 208 weeks.Different dose escalation schedules based on participants' APOE ε4 carrier status (carrier vs noncarrier) and the treatment received during the doubleblind part of the study (105 mg gantenerumab, 225 mg gantenerumab, or placebo) were used to reach the target dose of 1,200 mg gantenerumab Q4W.For this reason, gantenerumab doses and PK sampling schedules were different during the first 6 months of the OLE.Following Week 28, all participants were to receive doses of 1,200 mg gantenerumab Q4W, and PK and plasma concentrations were measured at Weeks 53,101,104,116,156,and 208.Overall, the observed PK profile was in agreement with the previously observed gantenerumab PK profile at doses of 105 and 225 mg administered in the double-blind part of the study (Supplementary Table 9).

Exploratory biomarkers in the double-blind part
In the double-blind part, treatment with gantenerumab led to a significant decrease from baseline to Week 104 in p-tau levels compared with placebo.For p-tau, the median change from baseline to Week 104 was -16.3% (n = 12) for gantenerumab and 1.41% (n = 20) for placebo.A numerical, but nonsignificant, decrease in t-tau levels was observed in participants treated with gantenerumab when compared with placebo.For t-tau, the median change from baseline to Week 104 was -6.17% (n = 12) for gantenerumab and 3.87% (n = 20) for placebo.No significant change was seen for Aβ42 and Aβ40 in either treatment group.

Supplementary
Coagulation (prothrombin time) Lumbar puncture m,n and CSF sampling n,o Note: At the BL visit, all safety assessments must be conducted on the day of dosing and all other assessments may be conducted up to 7 days earlier.On Day 4, the visit window is ± 1 day.The visit window is ± 7 days for all other visits.
a For participants who terminate early, the assessments from Wk 104 should be used.
b The MR PET substudy and Ccardiac PET substudy are optional, and participants who elect to participate must sign a separate informed consent.
c Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), smoking history, use of alcohol and drugs of abuse; and all medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, nutritional supplements) used by the participant within 6 months prior to the screening visit.Demographics include age, sex, and self-reported race/ethnicity.d At screening, three mandatory 3 mL whole blood samples will be obtained for DNA extraction for analysis of APOE ε4 status and Fcγ receptor genotype.
e Optional RCR samples for exploratory analysis from consenting participants should be obtained at the same time that the blood samples are obtained.
f Vital signs include HR and BP and at screening, Day 1, and unscheduled visits also include body temperature.The same arm should be used for all BP measurements.HR and BP should not be measured unless 15 minutes have passed since the last blood draw.Weight will only be collected at screening and Wk 104 visits.
g Perform after the participant has been in a supine position for 5 minutes.ECGs for each participant should be obtained from the same machine, whenever possible, and performed prior to any blood draws, brain MRI scans, and lumbar puncture.
i Hematology includes hemoglobin, hematocrit, red blood cell (with morphology), WBCs, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBC-other total counts.j The BL sample will be obtained prior to first dose.All PK samples except the Day 4 sample should be obtained just before administration of study drug (gantenerumab or placebo) or during the specified visits, if possible.Accurate recording of the time of study drug administration and PK sampling is critical.k Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and pH.Microscopic examination performed at the central laboratory if blood and/or protein results are positive or strongly positive.
l Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose administration.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.
m Lumbar puncture must be performed in the morning (between 8:00 a.m. and 12:00 p.m.), to minimize potential diurnal variation of CSF parameters.Lumbar puncture should be performed 10-20 days after dosing.
n CSF sampling and MRI (and PET scan if the participant is enrolled in any of the PET substudies) at screening should be performed once all other screening results are available and none exclude the participant from the trial.For participants enrolled in any of the PET substudies, PET may be performed after the lumbar puncture and prior to when CSF results are received; there is no requirement for CSF results to be available before the PET.After aliquoting the required samples, any remaining CSF fluid from consenting participants will be kept for future RCR biomarker research.
o CSF samples are mandatory at screening; collection at Wk 52 is optional.p MRI should not be performed for 3 days following a lumbar puncture.MRI scans must be performed within a maximum of 20 days after dose administration and results made available and reviewed before the next scheduled dose.The final MRI should be performed approximately 4 weeks before the final follow-up visit, to allow for review before the final visit.
q Includes volumetric MRI outcome measures.r Includes functional MRI outcome measures.
s Scale requires caregiver input or support.
t The SymptomGuide™ Facilitated GAS will be conducted at investigational sites in French-and English-speaking countries.
u Study drug administration should be performed only after all assessments/rating scales for the participant are completed (unless indicated otherwise).Study drug will be administered to participants as SC injection to the abdomen.Study personnel administering study drug must not be involved with any efficacy assessments or safety evaluations.Following the first four doses, participants should be observed for a minimum of 2 hours after dosing; for the remaining doses, participants should be observed for a minimum of 1 hour.On days when only safety is being assessed, participants may have the option to have the study drug administered and applicable safety assessments conducted at a prearranged location away from the site by a trained healthcare professional, if consent is obtained.Lumbar puncture i,j and CSF sampling j,k Note: The visit window is ± 7 days for all visits.
a For participants who terminate early, the unscheduled visit assessments should be used.
b Vital signs include HR and BP, and at unscheduled visits also include body temperature.The same arm should be used for all BP measurements.HR and BP should not be measured unless 15 minutes have passed since the last blood draw.Weight will only be collected at screening and Wk 104 visits.c Perform after the participant has been in a supine position for 5 minutes.ECGs for each participant should be obtained from the same machine, whenever possible, and performed prior to any blood draws, brain MRI scans, and lumbar puncture.
e Hematology includes hemoglobin, hematocrit, red blood cell (with morphology), WBCs, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBC-other total counts.f A PK sample will be obtained at unscheduled visits.

MMSE
g Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and pH.Microscopic examination performed at the central laboratory if blood and/or protein results are positive or strongly positive.
h Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose administration.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.
i Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon [12:00 p.m.]), to minimize potential diurnal variation of CSF parameters.Lumbar puncture should be performed 10-20 days after dosing.j For participants enrolled in any of the PET substudies, PET may be performed after the lumbar puncture and prior to CSF results are received; there is no requirement for CSF results to be available before the PET.After aliquoting the required samples, any remaining CSF fluid from consenting participants will be kept for future RCR biomarker research.p The SymptomGuide™ Facilitated GAS will be conducted at investigational sites in French-and English-speaking countries.
q Study drug administration should be performed only after all assessments/rating scales for the participant are completed (unless indicated otherwise).Study drug will be administered to participants as SC injection to the abdomen.Study personnel administering study drug must not be involved with any efficacy assessments or safety evaluations.Following the first four doses, participants should be observed for a minimum of 2 hours after dosing; for the remaining doses, participants should be observed for a minimum of 1 hour.On days when only safety is being assessed, participants may have the option to have the study drug administered and applicable safety assessments conducted at a prearranged location away from the site by a trained healthcare professional, if consent is obtained.
Note: The visit window is ± 7 days for all visits.
a First open-label gantenerumab dose administered following signature of the OLE ICF.
b Participants who continue OLE beyond the initial 2 years will need to complete OLE Week 104 assessments as per Supplementary Table 2g.
c Informed consents have to be signed prior to participants starting open label, including an ICF to the PET substudy for those participants participating in the PET substudies.Participants who complete the initial 2 years of OLE and who will not be continuing treatment extension will have their last PET scan 1 year after their last dose.a First open-label gantenerumab dose administered following signature of the OLE ICF.
b Participants who continue OLE beyond the initial 2 years will need to complete OLE Week 104 assessments as per Supplementary Table 2g.
c Informed consents have to be signed prior to participants starting open label, including an ICF to the PET substudy for those participants participating in the PET substudies.Participants who complete the initial 2 years of OLE and who will not be continuing treatment extension will have their last PET scan 1 year after their last dose.d MRI scans during up-titration (including the MRI scan 3 months post 1,200 mg) or following re-dosing after ARIA findings have resolved must be performed 10-20 days after dose administration.Other scheduled MRI scans must be performed within 20 days after dose administration and results made available and reviewed before the next scheduled dose.The final MRI should be performed approximately 4 weeks before the final follow-up visit, to allow for review before the final visit.
e Includes volumetric and functional MRI outcome measures.
f A safety MRI should be collected at Week 76.
g APOE results (carrier vs noncarriers) should be revealed and appropriate counseling offered to the participant.h Vital signs include HR and BP.The same arm should be used for all BP measurements.HR and BP should not be measured unless 15 minutes have passed since the last blood draw.Weight will only be collected at the OLE Week 104 visit.
i Perform after the participant has been in a supine position for 5 minutes.ECGs for each participant should be obtained from the same machine, whenever possible, and performed prior to any blood draws, brain MRI scans, and lumbar puncture.j Serum chemistry includes AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).At OLE Weeks 48 and 104, hemoglobin A1c, folic acid, vitamin B12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed.Hematology includes hemoglobin, hematocrit, red blood cell (with morphology), WBCs, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and  a First open-label gantenerumab dose administered following signature of the OLE ICF.
b Participants who continue OLE beyond the initial 2 years will need to complete OLE Week 104 assessments as per Supplementary Table 2g.
c Informed consents have to be signed prior to participants starting open label, including an ICF to the PET substudy for those participants participating in the PET substudies.Participants who complete the initial 2 years of OLE and who will not be continuing treatment extension will have their last PET scan 1 year after their last dose.
d MRI scans during up-titration (including the MRI scan 3 months post 1,200 mg) or following re-dosing after ARIA findings have resolved must be performed 10-20 days after dose administration.Other scheduled MRI scans must be performed within 20 days after dose administration and results made available and reviewed before the next scheduled dose.The final MRI should be performed approximately 4 weeks before the final follow-up visit, to allow for review before the final visit.e Optional MRI.
f Includes volumetric and functional MRI outcome measures.
g A safety MRI should be collected at Week 76.
h APOE results (carrier vs noncarriers) should be revealed and appropriate counseling offered to the participant.l Vital signs include HR and BP.The same arm should be used for all BP measurements.HR and BP should not be measured unless 15 minutes have passed since the last blood draw.Weight will only be collected at the pre-OLE and Week 104 visits.j Perform after the participant has been in a supine position for 5 minutes.ECGs for each participant should be obtained from the same machine, whenever possible, and performed prior to any blood draws, brain MRI scans, and lumbar puncture.
k Serum chemistry includes AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).At Weeks 48 and 104, hemoglobin A1c, folic acid, vitamin B12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed.Hematology includes hemoglobin, hematocrit, red blood cell (with morphology), WBCs, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBCother total counts.l At all visits when PK and ADA samples (including PK obtained for ARIA findings) are needed, the samples should be obtained just before administration of gantenerumab, unless at Weeks 53 and 101.Accurate recording of the time of study drug administration and PK sampling is critical.
m Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose administration.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.
n Lumbar puncture at Weeks 52 and 104 are optional.Lumbar puncture must be performed in the morning (between 8:00 a.m. and 12:00 p.m.), to minimize potential diurnal variation of CSF parameters.Lumbar puncture should be performed 10-20 days after dosing.
o Serum chemistry and hematology and listed efficacy scales should be obtained prior to first dose open label if these assessments were obtained more than 6 months ago.
p From Weeks 56-100, C-SSRS should only be obtained at Week 72.C-SSRS may be obtained at any time deemed necessary by the investigator.
q Patients participating in the PET substudies and whose last PET was more than 9 months ago will need a pre-OLE PET scan prior to starting the OLE.
Serum chemistry and hematology j a First open-label gantenerumab dose administered following signature of the OLE ICF.
b Participants who continue OLE beyond the initial 2 years will need to complete OLE Week 104 assessments as per Supplementary Table 2g.c Informed consents have to be signed prior to participants starting open label, including an ICF to the PET substudy for those participants participating in the PET substudies.Patients who complete the initial 2 years of OLE and who will not be continuing treatment extension will have their last PET scan 1 year after their last dose.
d MRI scans during up-titration (including the MRI scan 3 months post 1,200 mg) or following re-dosing after ARIA findings have resolved must be performed 10-20 days after dose administration.Other scheduled MRI scans must be performed within 20 days after dose administration and results made available and reviewed before the next scheduled dose.The final MRI should be performed approximately 4 weeks before the final follow-up visit, to allow for review before the final visit.
e Includes volumetric and functional MRI outcome measures.
f A safety MRI should be collected at Week 76.
g APOE results (carrier vs noncarriers) should be revealed and appropriate counseling offered to the participant.
h Vital signs include HR and BP.The same arm should be used for all BP measurements.HR and BP should not be measured unless 15 minutes have passed since the last blood draw.Weight will only be collected at the pre-OLE and Week 104 visits.l Perform after the participant has been in a supine position for 5 minutes.ECGs for each participant should be obtained from the same machine, whenever possible, and performed prior to any blood draws, brain MRI scans, and lumbar puncture.j Serum chemistry includes AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).At Weeks 48 and 104, hemoglobin A1c, folic acid, vitamin B12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed.Hematology includes Physical exam q x q x x hemoglobin, hematocrit, red blood cell (with morphology), WBCs, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and  Note: The visit window is ± 7 days for all visits.However, the minimum time between doses is 21 days, and the target day for each visit is timed with respect to baseline, not the prior visit.
a Follow-up visits should be obtained 4 and 16 weeks after last dose.

Supplementary Table 4
ARIA-E events in the OLE by dosing step, titration regimen, and APOE ε4 status (safety-evaluable population with post-baseline MRI in the OLE)

(
Alzheimer's Disease Activity Scale-Cognitive subscale 13 [ADAS-Cog 13]) and function (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]).The key secondary efficacy endpoints in the double-blind part included clinical decline and disease progression by assessment of Mini-Mental State Exam (MMSE), ADCS-ADL instrumental activities of daily living (IADL), Clinical Dementia Rating scale (CDR)-Sum of Boxes (CDR-SB) and ADAS-Cog 13 responders at Week 104.
with BGTS ≤4 With ARIA-E leading to no up-titration With ARIA-E leading to dose interruption Total no. of ARIA-E events -Mental State Exam; MRI, magnetic resonance imaging; OLE, open-label extension.

Table 1
Complete inclusion and exclusion criteria for the double-blind part and OLE Schedule of assessments in (a, b) the MR double-blind part and (c-g) the OLE a) Double-blind Year 1 ® assay Aβ, amyloid-β; AD, Alzheimer's disease; ADRDA, Alzheimer's Disease and Related Disorders Association; ARIA-E, amyloid-related imaging abnormalities -edema; ß-hCG, beta-human chorionic gonadotropin; CDR-GS, Clinical Dementia Rating Scale -Global Score; CSF, cerebrospinal fluid; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Version 5; FLAIR, fluid-attenuated inversion recovery; IEC, independent ethics committee; IRB, institutional review board; MMSE, Mini-Mental State Exam; MRI, magnetic resonance imaging; MR, Marguerite RoAD; NINCDS, National Institute of Neurological and Communicative Disorders and Stroke; OLE, open-label extension; PET, positron emission tomography.
k CSF samples are mandatory at Wk 104; collection at Wk 152 is optional.l MRI should not be performed for 3 days following a lumbar puncture.MRI scans must be performed 20 days after dose administration and results available and reviewed before the next scheduled dose.The final MRI should be performed ~4 weeks before the final follow-up visit, to allow for review before the final visit.
m Includes volumetric MRI outcome measures.n Includes functional MRI outcome measures.o Scale requires caregiver input or support.
d MRI scans during up-titration (including the MRI scan 3 months post 1,200 mg) or following re-dosing after ARIA findings have resolved must be performed 10-20 days after dose administration.Other scheduled MRI scans must be performed within 20 days after dose administration and results made available and reviewed before the next scheduled dose.The final MRI should be performed approximately 4 weeks before the final follow-up visit, to allow for review before the final visit.At all visits when PK and ADA samples (including PK obtained for ARIA findings) are needed, the samples should be obtained just before administration of gantenerumab, unless at Weeks 53 and 101.Accurate recording of the time of study drug administration and PK sampling is critical.Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose administration.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.From Weeks 56-100, C-SSRS should only be obtained at Week 72.C-SSRS may be obtained at any time deemed necessary by the investigator.p Participants participating in the PET substudies and whose last PET was more than 9 months ago will need a pre-OLE PET scan prior to starting the OLE.q Physical and neurologic exams prior to OLE are optional.d) OLE Years 1 and 2 (participants previously on 225 mg gantenerumab: noncarriers) e Includes volumetric and functional MRI outcome measures.f A safety MRI should be collected at Week 76. g APOE results (carrier vs noncarriers) should be revealed and appropriate counseling offered to the participant.h Vital signs include HR and BP.The same arm should be used for all BP measurements.HR and BP should not be measured unless 15 minutes have passed since the last blood draw.Weight will only be collected at the OLE Week 104 visit.i Perform after the participant has been in a supine position for 5 minutes.ECGs for each participant should be obtained from the same machine, whenever possible, and performed prior to any blood draws, brain MRI scans, and lumbar puncture.j Serum chemistry includes AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).At OLE Weeks 48 and 104, hemoglobin A1c, folic acid, vitamin B12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed.Hematology includes hemoglobin, hematocrit, red blood cell (with morphology), WBCs, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBCother total counts.k Serum chemistry and hematology and listed efficacy scales should be obtained prior to first dose open label if these assessments were obtained more than 6 months ago.l m n Lumbar puncture at Weeks 52 and 104 are optional.Lumbar puncture must be performed in the morning (between 8:00 a.m. and 12:00 p.m.), to minimize potential diurnal variation of CSF parameters.Lumbar puncture should be performed 10-20 days after dosing.o Rating Scale; ECG, electrocardiogram; HR, heart rate; ICF, informed consent form; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; OLD, Open Label Day; OLE, open-label extension; OLW, Open Label Week; PET, positron emission tomography; PK, pharmacokinetic; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamate pyruvate transaminase; UV, unscheduled visit; WBC, white blood cell.Note: The visit window is ± 7 days for all visits.
Serum chemistry and hematology and listed efficacy scales should be obtained prior to first dose open label if these assessments were obtained more than 6 months ago.lAt all visits when PK and ADA samples (including PK obtained for ARIA findings) are needed, the samples should be obtained just before administration of gantenerumab, unless at Weeks 53 and 101.Accurate recording of the time of study drug administration and PK sampling is critical.mFemales of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose administration.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.nLumbar puncture at Weeks 52 and 104 are optional.Lumbar puncture must be performed in the morning (between 8:00 a.m. and 12:00 p.m.), to minimize potential diurnal variation of CSF parameters.Lumbar puncture should be performed 10-20 days after dosing.) OLE Years 1 and 2 (participants previously on 105 mg gantenerumab or placebo: carriers) k o From Weeks 56-100, C-SSRS should only be obtained at Week 72.C-SSRS may be obtained at any time deemed necessary by the investigator.p Participants participating in the PET substudies and whose last PET was more than 9 months ago will need a pre-OLE PET scan prior to starting the OLE.q Physical and neurologic exams prior to OLE are optional.eNote: The visit window is ± 7 days for all visits.
Note: The visit window is ± 7 days for all visits.
WBCother total counts.kSerum chemistry and hematology and listed efficacy scales should be obtained prior to first dose open label if these assessments were obtained more than 6 months ago.lAt all visits when PK and ADA samples (including PK obtained for ARIA findings) are needed, the samples should be obtained just before administration of gantenerumab, unless at Weeks 53 and 101.Accurate recording of the time of study drug administration and PK sampling is critical.mFemales of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose administration.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.nLumbar puncture at Weeks 52 and 104 are optional.Lumbar puncture must be performed in the morning (between 8:00 a.m. and 12:00 p.m.), to minimize potential diurnal variation of CSF parameters.Lumbar puncture should be performed 10-20 days after dosing.o From Weeks 56-100, C-SSRS should only be obtained at Week 72.C-SSRS may be obtained at any time deemed necessary by the investigator.p Participants participating in the PET substudies and whose last PET was more than 9 months ago will need a pre-OLE PET scan prior to starting the OLE.q Physical and neurologic exams prior to OLE are optional.
The follow-up visit at 16 weeks is not required for participants who enroll in Open RoAD (open-label rollover study).b Participants who continue OLE beyond the initial 2 years to the treatment extension should sign an ICF prior to Week 104.c MRI scans during up-titration (including the MRI scan 3 months post 1,200 mg) or following re-dosing after ARIA findings have resolved must be performed 10-20 days after dose administration.Other scheduled MRI scans must be performed within 20 days after dose administration and results made available and reviewed before the next scheduled dose.The final MRI should be performed approximately 4 weeks before the final follow-up visit, to allow for review before the final visit.Vital signs include HR and BP.The same arm should be used for all BP measurements.HR and BP should not be measured unless 15 minutes have passed since the last blood draw.Weight will be collected yearly at the time of physical exam.Perform after the participant has been in a supine position for 5 minutes.ECGs for each participant should be obtained from the same machine, whenever possible, and performed prior to any blood draws, brain MRI scans, and lumbar puncture.g Serum chemistry includes AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).At OLE Weeks 48 and 104, hemoglobin A1c, folic acid, vitamin B12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed.Hematology includes hemoglobin, hematocrit, red blood cell (with morphology), WBCs, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBCother total counts.h At all visits where PK and ADA samples (including PK obtained for ARIA findings) are needed, the samples should be obtained just before administration of gantenerumab.Accurate recording of the time of study drug administration and PK sampling is critical.Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose administration.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.Lumbar puncture at Week 104 is optional.Lumbar puncture must be performed in the morning (between 8:00 a.m. and 12:00 p.m.), to minimize potential diurnal variation of CSF parameters.Lumbar puncture should be performed 10-20 days after dosing.
dIncludes volumetric and functional MRI outcome measures.e f i j C-SSRS should be obtained every 6 months or at any time deemed necessary by the investigator.k Patients participating in the PET substudy will have a final PET scan at OLE Week 156.l

E event With ARIA-E event with BGTS ≤4 With ARIA-E leading to no up-titration With ARIA-E leading to dose interruption Total no. of ARIA-E events
All values are n (%) unless otherwise stated.APOE ε4, apolipoprotein E ε4 allele; ARIA-E, amyloid-related imaging abnormalities -edema; MRI, magnetic resonance imaging; OLE, openlabel extension.AEs associated with ARIA-E MRI findings and retrieved using a post hoc programmatic approach (safety-evaluable participants with post-baseline MRI in OLE) Total (N = 219) All values are n (%) unless otherwise stated.AE, adverse event; ARIA-E, amyloid-related imaging abnormalities-edema; MRI, magnetic resonance imaging; OLE, open-label extension.Cog 13, Alzheimer's Disease Assessment Scale -Cognitive Subscale 13; ADCS-ADL, Alzheimer's Disease Cooperative Study -Activities of Daily Living; CDR-GS, Clinical Dementia Rating -Global Score; CDR-SB, Clinical Dementia Rating -Sum of Boxes; MMSE, Mini-Mental State Examination; OLE, open-label extension; SD, standard deviation.