Safety and Efficacy Study of Gantenerumab in Participants With Early Alzheimer's Disease (AD)

• ClinicalTrials.gov Identifier: NCT03443973
• Recruitment Status: Active, not recruiting
• First Posted: February 23, 2018
• Last Update Posted: July 6, 2022
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: February 19, 2018
• First Posted Date: February 23, 2018
• Last Update Posted Date: July 6, 2022
• Actual Study Start Date: August 22, 2018
• Estimated Primary Completion Date: September 21, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 15, 2020): Change From Baseline to Week 116 in Global Outcome, as Measured by Clinical Dementia Rating-Sum of Boxes (CDR-SOB) [ Time Frame: Baseline up to Week 116 ]
• Original Primary Outcome Measures (submitted: February 19, 2018): Change From Baseline to Week 104 in Clinical Dementia Rating-Sum of Boxes (CDR-SOB) Score [ Time Frame: Baseline up to Week 104 ]

Current Secondary Outcome Measures (submitted: September 6, 2021)

• Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score [ Time Frame: Baseline up to Week 116 ]
• Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Subscale Score [ Time Frame: Baseline up to Week 116 ]
• Change from Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition, Subscale 13 (ADAS-Cog13) [ Time Frame: Baseline up to Week 116 ]
• Change From Baseline to Week 116 in Verbal Fluency Task Score [ Time Frame: Baseline up to Week 116 ]
• Change From Baseline to Week 116 in Coding [ Time Frame: Change from baseline to Week 116 in the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) coding subtest. ]
• Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score [ Time Frame: Baseline to Week 116 ]
• Change From Baseline to Week 116 in Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) Total Score [ Time Frame: Baseline up to Week 116 ]
• Percentage of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to end of study (week 164) or Week 35 (Open label extension) ]
• Change in Columbia-Suicide Severity Rating Scale (C-SSRS) Score [ Time Frame: Baseline up to Week 116 or Week 24 in Open label extension ]
• Percentage of Participants with Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to end of study (week 164) or Week 35 (Open label extension) ]
• Percentage of Participants with Amyloid-Related Imaging Abnormalities-Haemosiderin deposition (ARIA-H) Confirmed by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to end of study (week 164) or Week 35 (Open label extension) ]
• Percentage of Participants with Injection-Site Reactions [ Time Frame: Baseline up to end of study (week 164) or Week 35 (Open label extension) ]
• Percentage of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab [ Time Frame: Baseline up to end of study (week 164) or Week 35 (Open label extension) ]
• Change from Baseline in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan in a subset of patients up to Week 116 [ Time Frame: Baseline up to Week 116 ]
• Change From Baseline in Brain Tau Load, as Measured by Tau PET Scan in a Subset of Patients up to Week 116 [ Time Frame: Baseline up to Week 116 ]
• Change From Baseline in CSF Marker of Disease in a Subset of Patients - Total Tau up to Week 116 [ Time Frame: Baseline up to Week 116 ]
• Change From Baseline in CSF Marker of Disease in a Subset of Patients - Phosphorylated Tau up to Week 116 [ Time Frame: Baseline up to Week 116 ]

Original Secondary Outcome Measures (submitted: February 19, 2018)

• Change From Baseline to Week 104 in Alzheimer Disease Assessment Scale-Cognition 11 (ADAS-Cog11) Subscale Score [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline to Week 104 in Mini-Mental State Examination (MMSE) Total Score [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline to Week 104 in Alzheimer Disease Assessment Scale-Cognition 13 (ADAS-Cog13) Subscale Score [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline to Week 104 in Verbal Fluency Task Score [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline to Week 104 in Functional Activities Questionnaire (FAQ) Score [ Time Frame: Baseline to Week 104 ]
• Change From Baseline to Week 104 in Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) Total Score [ Time Frame: Baseline up to Week 104 ]
• Percentage of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to end of study (up to Week 152) ]
• Percentage of Participants With Anti-Drug Antibodies (ADA) to Gantenerumab [ Time Frame: Baseline up to end of study (up to Week 152) ]
• Plasma Concentration of Gantenerumab [ Time Frame: Pre-dose (0 hour [hr]) at Baseline (Day 1), Weeks 24, 52, 76; and at Weeks 2, 41, 103, 116, early termination visit (up to Week 152) ]
• Change From Baseline in Brain Amyloid Load, as Measured by Amyloid Positron Emission Tomography (PET) Scan up to Week 104 [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline in Brain Tau Load, as Measured by Tau PET Scan up to Week 104 [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline in Cerebral Spinal Fluid (CSF) Marker of Disease - Amyloid-beta 1-42 (Aβ1-42) up to Week 104 [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline in CSF Marker of Disease - Total Tau up to Week 104 [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline in CSF Marker of Disease - Phosphorylated Tau up to Week 104 [ Time Frame: Baseline up to Week 104 ]
• Change From Baseline in Volumetric Magnetic Resonance Imaging (MRI) up to Week 104 [ Time Frame: Baseline up to Week 104 ]
  MRI will be used to assess the effect of treatment on volume of whole brain, ventricles, hippocampus, or other structures.

Current Other Pre-specified Outcome Measures (submitted: September 6, 2021)

Plasma Concentration of Gantenerumab [ Time Frame: Baseline, Week 2, 24, 41, 52, 76, 103, 115, 128, 164, and at early termination and unscheduled visit, Week 1 and Week 24 (Open label extension) ]

Re-classified as 'Other Pre-specified' due to sparse PK sampling, to support population PK analysis of the data which is an exploratory analysis.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy Study of Gantenerumab in Participants With Early Alzheimer's Disease (AD)
• Official Title: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study of Gantenerumab in Patients With Early (Prodromal to Mild) Alzheimer's Disease
• Brief Summary: This randomized, double-blind, placebo-controlled, parallel group study will evaluate the efficacy and safety of gantenerumab versus placebo in participants with early (prodromal to mild) AD. All participants must show evidence of beta-amyloid pathology. Eligible participants will be randomized 1:1 to receive either subcutaneous (SC) injection of gantenerumab or placebo. The primary efficacy assessment will be performed at the end of the double blind period at week 116. Participants will then be offered to enter into an open-label extension (OLE). Participants not willing to go to the OLE will participate in a long term follow-up period for up to 50 weeks after the last gantenerumab dose.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Alzheimer Disease

Intervention

• Drug: Gantenerumab
  Gantenerumab will be administered as per the schedule specified in the respective arm.
  Other Name: RO4909832
• Drug: Placebo
  Placebo matching to gantenerumab will be administered as per the schedule specified in the respective arm.

Study Arms

• Experimental: Gantenerumab
  Gantenerumab will be administered as SC injections with gradual uptitration.
  Intervention: Drug: Gantenerumab
• Placebo Comparator: Placebo
  Placebo will be administered as SC injections with gradual uptitration.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 6, 2021): 982
• Original Estimated Enrollment (submitted: February 19, 2018): 750
• Estimated Study Completion Date: August 23, 2023
• Estimated Primary Completion Date: September 21, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion criteria:

• Meets National Institute on Aging/Alzheimer's Association (NIAAA) core clinical criteria for probable AD dementia or prodromal AD (consistent with the NIAAA diagnostic criteria and guidelines for mild cognitive impairment)
• Evidence of the AD pathological process, as confirmed by CSF tau/A-beta42or amyloid PET scan
• Demonstrated abnormal memory function
• MMSE score greater than or equal to 22 (≥ 22)
• Clinical dementia rating-global score (CDR-GS) of 0.5 or 1.0
• Availability of a reliable study partner who accepts to participate in study procedures throughout the 2 years duration of study
• If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening and until randomization
• For enrollment in the China extension, patients must have residence in mainland China, Hong Kong, or Taiwan and be of Chinese ancestry
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods

Key Exclusion criteria:

• Any evidence of a condition other than AD that may affect cognition
• History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder
• History or presence of clinically evident systemic vascular disease that in the opinion of the investigator has the potential to affect cognitive function
• History or presence of clinically evident cerebrovascular disease
• History or presence of posterior reversible encephalopathy syndrome
• History or presence of any stroke with clinical symptoms within the past 12 months, or documented history within the last 6 months of an acute event that is consistent with a transient ischemic attack
• History of severe, clinically significant CNS trauma
• History or presence of intracranial mass (e.g., glioma, meningioma) that could potentially impair cognition
• Presence of infections that affect brain function or history of infections that resulted in neurologic sequelae
• History or presence of systemic autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits
• At risk for suicide in the opinion of the investigator
• Alcohol and/or substance abuse or dependants in past 2 years
• Relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities
• Any contraindications to brain MRI
• Unstable or clinically significant cardiovascular, kidney or liver disease
• Uncontrolled hypertension
• Unstable or clinically significant cardiovascular disease
• Abnormal thyroid function
• Patients with evidence of folic acid deficiency

Exclusion for Open-Label Extension (OLE):

• Discontinued from study treatment during the double-blind treatment period
• Received any other investigational medication during the double-blind treatment period or after the end of double-blind treatment
• Participation in the OLE deemed inappropriate by the investigator
• Presence of ARIA-E findings at the Week 116 MRI scan

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Belgium, Chile, Croatia, Denmark, Finland, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Singapore, Spain, Sweden, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03443973
• Other Study ID Numbers: WN39658; 2017-001365-24 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: July 2022