An Open-Label, Multicenter, Rollover Study to Evaluate the Safety, Tolerability, and Efficacy of Long-Term Gantenerumab Administration in Participants With Alzheimer's Disease
Trial Snapshot
- Phase
- Phase 3
- Status
- Terminated
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 1,382
- Locations
- 268
- Primary Endpoint
- Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI
Study Overview
Brief Summary
This is an open-label, multicenter, rollover study to evaluate the safety, tolerability, and efficacy of long-term administration of open-label gantenerumab in participants with AD who completed Study WN29922 or WN39658, either the double-blind or open-label extension (OLE) part.
Detailed Description
Participants who were in the active arm in the double blind part and those who have completed OLE part in the parent study, will continue receive open-label gantenerumab 510 mg sub-cutaneously (SC) every 2 weeks (Q2W). Participants who are naive to gantenerumab treatment will be required to undergo the 3 step uptitration scheme as in the parent study before receiving target dose of open label gantenerumab.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Completed Study WN29922 or WN39658, either its double-blind part or OLE part, and did not discontinue study drug early
- •The participant should be capable of completing assessments either alone or with the help of the caregiver
- •Availability of a person (referred to as the "caregiver")
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception methods with a failure rate of <1% per year (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices) during the treatment period and for at least 16 weeks after the final dose of gantenerumab
- •Agreement not to donate blood or blood products for transfusion for the duration of the study and for 1 year after final dose of study drug
Exclusion Criteria
- •Pregnant or breastfeeding, or intending to become pregnant during the study or within at least 16 weeks after the final dose of study drug
- •Prematurely discontinued from Study WN29922 or WN39658
- •Any medical condition that may jeopardize the participant's safety if he or she continues to receive study treatment
- •Received any investigational treatment other than gantenerumab during or since completion of Study WN29922 or WN39658, either its double-blind or OLE part
- •Evidence of disseminated leptomeningeal hemosiderosis
- •Evidence of intracerebral macrohemorrhage
- •Use of prohibited medication
- •Evidence of ARIA-E on the last MRI scan report in Study WN29922 or WN39658, either its double-blind or OLE part
Arms & Interventions
Group 1
Participants, who completed the double-blind part and did not enter the OLE part of Study WN29922 or WN39658, will be enrolled and receive open-label gantenerumab approximately 2 weeks after the Week 116 visit of Study WN29922 or WN39658. This will be considered the OLE baseline visit (OLE Day 1).
Intervention: Gantenerumab (Drug)
Group 2
Participants, who completed the double-blind part and the OLE part of Study WN29922 or WN39658, will be enrolled and receive open-label gantenerumab approximately 2 weeks after the OLE Week 34 visit or the final dose visit in the Study WN29922 or WN39658 OLE.
Intervention: Gantenerumab (Drug)
Outcomes
Primary Outcomes
Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Haemosiderin Deposition (ARIA-H) Confirmed by MRI
Time Frame: From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
Number of Participants With at Least One Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by MRI
Time Frame: From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. In ARIA-E, (E for oedema or effusion), oedema can be seen in different areas of the brain on MRI, representing fluid leakage into the brain parenchyma or sulcal spaces. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
Number of Participants With Injection-Site Reactions (ISRs)
Time Frame: From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a pharmaceutical product, regardless of casual attribution. Local injection reactions (or injection site reactions) are defined as AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
Number of Participants Who Discontinued the Study Due an AE
Time Frame: From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of casual attribution. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
Number of Participants With at Least One Adverse Event of Special Interest (AESI)
Time Frame: From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of casual attribution. AEs that were considered to be of special interest for this study included cases of potential drug-induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law and suspected transmission of an infectious agent by the study drug. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
Number of Participants With at Least One Adverse Event (AE) and Serious Adverse Event (SAE)
Time Frame: From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of casual attribution. A SAE is any AE that is fatal, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug or a significant medical event in the investigator's judgment. The first dosing visit in the OLE (first dosing in current study or first dosing in the OLE period of the parent GRADUATE studies) was considered as baseline (OLE Day 1).
Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) Score
Time Frame: From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks)
C-SSRS= assesses lifetime suicidality of participant (at baseline) \& any new instances of suicidality (since last visit). Structured interview prompts recollection of suicidal ideation (intensity of ideation, behavior, \& attempts with actual/potential lethality). Categories have yes/no responses, include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted/Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation/behavior= "yes" to any of listed categories. Score of 0= no suicide risk. Score of 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported here. First dosing visit in OLE (first dosing in current study or OLE period of parent GRADUATE studies)=baseline (OLE Day 1).
Secondary Outcomes
- Change From Baseline Over Time in Clinical Dementia Rating - Global Score (CDR-GS)(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Change From Baseline Over Time in Mini-Mental State Examination (MMSE) Score(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Change From Baseline Over Time in Alzheimer Disease Assessment Scale-Cognition, Subscale 13 (ADAS-Cog13) Score(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Change From Baseline Over Time in Verbal Fluency Task Score(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Change From Baseline Over Time in Clinical Dementia Rating (CDR) - Sum of Boxes (SB)(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Change From Baseline Over Time in Alzheimer Disease Assessment Scale-Cognition, Subscale 11 (ADAS-Cog11) Score(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Change From Baseline Over Time in Coding (Digit Symbol Substitution Test [DSST]) Subset(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Number of Participants With Anti-drug Antibody (ADA) to Gantenerumab(From Baseline (OLE Day 1) up to 14 weeks after the last dose (up to 134 weeks))
- Change in Functional Activities Questionnaire (FAQ) Score(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)
- Change in Alzheimer Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) Score(Baseline (OLE Day 1), Weeks 24, 36, 52, 76 and 104)