Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Two Year Study to Evaluate the Effect of Subcutaneous RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease With Option for up to an Additional Two Years of Treatment and an Open-Label Extension With Active Study Treatment
Overview
- Phase
- Phase 3
- Intervention
- Placebo
- Conditions
- Alzheimer's Disease
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 799
- Locations
- 139
- Primary Endpoint
- Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 104 (Double-Blind Treatment Phase)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This multi-center, randomized, double-blind, placebo-controlled parallel-group study will evaluate the effect of gantenerumab (RO4909832) on cognition and functioning and the safety and pharmacokinetics in participants with prodromal Alzheimer's Disease. Participants will be randomized to receive subcutaneous (SC) injections of either gantenerumab or placebo. Participants who consent to be part of the sub study will undergo positron emission tomography (PET) scanning to assess brain amyloid. The anticipated time on study treatment is 104 weeks in Part 1, with an option for an additional up to 2 years of treatment in Part 2, followed by an open-label extension (Part 3) until July 2020.
The dosing for Parts 1 and 2 was stopped after a planned futility interim analysis showed a low probability of meeting the primary outcome measure with the doses studied. The study has converted to open-label to investigate higher gantenerumab doses.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adult participants, 50-85 years of age
- •Participants with prodromal Alzheimer's disease who are not receiving memantine or cholinesterase inhibitors
- •Has a study partner who in the investigator's judgement has frequent and sufficient contact with the participant as to be able to provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at clinic visits which require partner input for scale completion
- •Has had sufficient education or work experience to exclude mental retardation
- •Study partner has noticed a recent gradual decrease in participant's memory (over the last 12 months), which the participant may or may not be aware of
- •Screening Mini Mental State Exam (MMSE) score of 24 or above
- •Additional inclusion criteria for sub study:
- •Able and willing to travel to PET imaging center and complete the planned scanning sessions
- •Past and planned exposure to ionizing radiation not exceeding safe and permissible levels
Exclusion Criteria
- •Other prior or current neurologic or medical disorder which may currently or during the course of the study impair cognition or psychiatric functioning
- •A history of stroke
- •A documented history of transient ischemic attack within the last 12 months
- •History of schizophrenia, schizoaffective or bipolar disorder
- •Currently meets criteria for major depression
- •Within the last 2 years, unstable or clinical significant cardiovascular disease (myocardial infarction, angina pectoris)
- •Additional exclusion criteria for sub study:
- •Inclusion in a research and/or medical protocol involving PET ligands or other radioactive agents within 12 months
- •Present or planned participation in a research and/or medical protocol involving PET ligands or radioactive agents other than study WN25203
- •Have planned or are planning to have exposure to ionizing radiation that in combination with the planned administration with study amyloid PET ligand would result in a cumulative exposure that exceeds local recommended exposure limits
Arms & Interventions
Placebo (Parts 1 and 2)
Participants with Alzheimer's disease received Placebo by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.
Intervention: Placebo
Gantenerumab 105 mg (Parts 1 and 2)
Participants with Alzheimer's disease received Gantenerumab 105 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.
Intervention: Gantenerumab
Gantenerumab 225 mg (Parts 1 and 2)
Participants with Alzheimer's disease received Gantenerumab 225 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2.
Intervention: Gantenerumab
Placebo (Parts 1 and 2) switched to Gantenerumab Up to 1200mg (Part 3 Open-Label Extension [OLE])
Participants with Alzheimer's disease who had received Placebo by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.
Intervention: Gantenerumab
Gantenerumab Up to 1200 mg (Part 3 Open-Label Extension [OLE])
Participants with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.
Intervention: Gantenerumab
Outcomes
Primary Outcomes
Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 104 (Double-Blind Treatment Phase)
Time Frame: Baseline, Week 104
The CDR (Clinical Dementia Rating) is obtained through semi-structured interviews of participants and informants, and cognitive functioning is rated in six domains of functioning: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. The CDR-SOB (Clinical Dementia Rating-Sum of Boxes) is based on summing each of the domain box scores with total scores ranging from 0-18, where lower total scores represent better outcomes and higher total scores represent worse outcomes.
Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) (OLE Phase)
Time Frame: Baseline up until a maximum of 5 years
An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Secondary Outcomes
- Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog-13) Scores at Week 156 (OLE Phase)(Baseline, Week 156)
- Mean Change From Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Percentage Change From Baseline in Cerebrospinal Fluid Biomarkers (Phosphorylated-tau [P-tau], Amyloid Beta 1-42 [Abeta 1-42], Total Tau [T-tau]) at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Percentage Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156 (Double-Blind Treatment Phase)(Baseline, Week 156)
- Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 156 (OLE Phase)(Baseline, Week 156)
- Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 156 (OLE Phase)(Baseline, Week 156)
- Time to Onset of Dementia at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Mean Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Composite Score at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Percentage Change From Baseline in Hippocampal Volume at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Gantenerumab Plasma Concentrations at Different Time Points (OLE Phase)(Pre-Dose: Weeks 64, 100, 104, 136, 156 and 208; Post-Dose: Week 101)
- Mean Change From Baseline in CDR-Global Score at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Percentage of Participants With Anti-Drug Antibodies (ADAs) (Double-Blind Treatment Phase)(Baseline up until a maximum of 4.5 years)
- Time to Onset of Dementia at Week 156 (OLE Phase)(Baseline, Week 156)
- Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 156 (OLE Phase)(Baseline, Week 156)
- Percentage of Participants With Anti-Drug Antibodies (ADAs) (OLE Phase)(Baseline up until a maximum of 5 years)
- Mean Change From Baseline in Neuropsychiatric Inventory (NPI) Questionnaire Score at Week 104 (Double-Blind Treatment Phase)(Baseline, Week 104)
- Gantenerumab Plasma Concentrations at Different Time Points (Double-Blind Treatment Phase)(Pre-Dose: Weeks 8, 20, 44, 68 and 100; Post-Dose: Weeks 1, 53 and 101)
- Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) (Double-Blind Treatment Phase)(Baseline up until a maximum of 4.5 years)
- Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 156 (OLE Phase)(Baseline, Week 156)
- Mean Change From Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 156 (OLE Phase)(Baseline, Week 156)
- Percentage Change From Baseline in Hippocampal Volume at Week 152 (OLE Phase)(Baseline, Week 152)
- Mean Change From Baseline in CDR-Global Score at Week 156 (OLE Phase)(Baseline, Week 156)
- Percentage Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156 (OLE Phase)(Baseline, Week 156)