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A Phase III, Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Gantenerumab in Participants at Risk for or at the Earliest Stages of Alzheimer's Disease

A Study to Evaluate the Efficacy and Safety of Gantenerumab in Participants at Risk for or at the Earliest Stages of Alzheimer's Disease (AD)

25

Participants aged 60-80 years with evidence Amyloid beta pathology, cognitively unimpaired. The mean age of participants was 71.8 years, with 8 males (32.0%) and 17 females (68.0%).

In this study, 25 participants (13 participants in gantenerumab group, and 12 participants in placebo group) were randomized. Participants in this study could choose dosing regimens for the target dose: either 255 mg every 1 week (Q1W) or 510 mg every 2 weeks (Q2W). The former regimen involved administering at least 3 doses of gantenerumab 120 mg every 4 weeks(Q4W), at least 3 doses of 255 mg Q4W, and at least 6 doses of 255 mg Q2W, followed by gantenerumab 255 mg Q1W. The latter regimen involved administering at least 3 doses of gantenerumab 120 mg Q4W, at least 3 doses of 255 mg Q4W, and at least 3 doses of 510 mg Q4W, followed by gantenerumab 510 mg Q2W. Following the negative results of WN29922 (NCT03444870) and WN39658 (NCT03443973) studies of patients with prodromal or mild Alzheimer's disease, this study (WN42444 [NCT05256134]) was stopped early by Sponsor. Although 1200 participants were planned to be enrolled, only 25 participants were enrolled in this study. In addition, although the administration period was planned for 210 weeks, the maximum duration of administration was 27 weeks, and no participants reached the target dose.

Overall, 5 out of 13 (38.5%) participants who received gantenerumab, and 6 out of 12 (50.0%) participants who received placebo had at least one adverse event (AE). One out of 13 participants who received gantenerumab (injection-site reaction; 7.7%), and 1 out of 12 participants who received placebo (pain; 8.3%) had one treatment-related AE, respectively. These AEs were mild and the participants recovered quickly. Amyloid-related imaging abnormality-edema/effusion (ARIA-E), amyloid-related imaging abnormality-hemosiderin deposition (ARIA-H) and injection-site reaction were considered identified risk for gantenerumab. No one had ARIA-E MRI findings and 1 out 13 (7.7%) participants who received gantenerumab had an ARIA-H MRI finding. As previously mentioned, 1 out of 13 (7.7%) participants who received gantenerumab had injection-site reaction. No serious AE occurred during this study, no one stopped taking the study drug because of the treatment-related AEs, and no deaths occurred during the study.

Primary outcome measures: The change in cognition from baseline to Year 4, as measured by the Preclinical Alzheimer's Cognitive Composite-5 score. As this study was stopped early, not enough participants had taken part, no one was dosed for more than 27 weeks and therefor participants in gantenerumab group did not reach the target dose. For this reason, no conclusion can be made on the efficacy measure in this study. Secondary outcome measures: The change in cognition and function from baseline to Year 4, time from randomization to onset of confirmed clinical progression, and the safety over for 4 years. Regarding the efficacy evaluation, due to the reasons mentioned above, no conclusion can be made in this study. For the safety evaluation, refer to Adverse events.

As this study was stopped early, not enough participants had taken part, no one was dosed for more than 27 weeks and therefor participants in gantenerumab group did not reach the target dose. For this reason, no conclusion can be made on the efficacy measure in this study. All treatment-related AEs (pain and injection-site reaction) were mild and the participants who had treatment-related AEs recovered quickly.

Yes

Qualified researchers may request access to individual patient level data through the clinical study data request platform. For further details on Chugai's Data Sharing Policy and how to request access to related clinical study documents, see here (www.chugai-pharm.co.jp/english/profile/rd/ctds_request.html).

https://jrct.niph.go.jp/latest-detail/jRCT2031220468

Gesine Respondek, M.D.

F. Hoffmann-La Roche Ltd

1-1 NIHONBASHI-MUROMACHI 2-CHOME, CHUO-KU, Tokyo

clinical-trials@chugai-pharm.co.jp

Clinical trials information

Chugai Pharmaceutical Co., Ltd.

1-1 NIHONBASHI-MUROMACHI 2-CHOME, CHUO-KU, Tokyo

+81-120-189-706

clinical-trials@chugai-pharm.co.jp

Complete

Jan. 30, 2023

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- Willing and able to comply with the study protocol and complete all aspects of the study [including cognitive and functional assessments, physical and neurological examinations, MRI, CSF collection, genotyping, and positron emission tomography (PET) imaging].
- Cognitively unimpaired with a screening clinical dementia rating global score (CDR-GS) of 0, and Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS DMI) >=80.
- Evidence of cerebral amyloid accumulation.
- Participants who have an available person (referred to as a "study partner").
- Fluent in the language of the tests used at the study site.
Adequate visual and auditory acuity, sufficient to perform neuropsychological testing (eye glasses and hearing aids are permitted).
- Agreed not to participate in other interventional research studies for the duration of this trial.
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 17 weeks after the final dose of study treatment.

- Any evidence of an underlying neurological or neurodegenerative condition that may lead to cognitive impairment other than AD.
- Clinical diagnosis of mild cognitive impairment (MCI), prodromal AD, or any form of dementia.
- History or presence of intracranial or intracerebral vascular malformations, aneurysm, subarachnoid hemorrhage, or intracerebral macrohemorrhage.
- History of major depression, schizophrenia, schizoaffective disorder, or bipolar disorder.
- History or presence of systemic autoimmune disorders that may lead to progressive neurological impairment with associated cognitive deficits.
- Current COVID-19 infection.
- Evidence of folic acid or vitamin B-12 deficiency.
- Any passive immunotherapy (Ig) or other long-acting biologic agent to prevent or postpone cognitive decline within 1 year of screening.
- Any other investigational treatment within 5 half-lives or 6 months (whichever is longer) prior to screening.
- Typical/Atypical anti-psychotic medications or neuroleptic medications.
- Anticoagulation medications within 3 months of screening with no plans to initiate any prior to randomization.
- Any previous treatment with cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists are exclusionary at screening.
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 17 weeks after the final dose of gantenerumab.
- Impaired coagulation.
- Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins, including gantenerumab and gantenerumab excipients.

Both

Preclinical AD

Gantenerumab: Gantenerumab will be administered as subcutaneous (SC) injection with gradual uptitration.
Placebo Comparator: Placebo will be administered as SC injection with gradual uptitration.

Efficacy
Change from Baseline to Year 4 in Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) Score

Safety, Efficacy, Phamacokinetics, Phamacodynamics, Other
1. Time from Randomization to Clinical Progression to Mild Cognitive Impairment (MCI) or Dementia due to AD
2. Time to Onset of Confirmed Clinical Progression
3. Change from Baseline to Year 4 in the A-IADL-Q-SV, CFIa, CDR-SB
4. Number of Participants with AEs, SAEs and AESIs
5. Number of Participants with Anti-Drug Antibodies (ADAs)
6. Change in Brain Amyloid, Tau Load Over Time in a Subset of Partcipants
7. Change in Cerebrospinal Fluid (CSF) Abeta 1-42, 1-40, NfL, pTau, tTau Over Time in a Subset of Participants
8. Change in Blood Abeta 1-42, 1-40, NfL, pTau Over Time
9. Change in Whole Brain, Ventricle, Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI)

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Sept. 08, 2022

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