GRADUATE I AND II: Findings of Two Phase III Randomized Placebo-controlled Studies Assessing the Efficacy and Safety of Subcutaneous Gantenerumab in Early Alzheimer’s Disease (AD) (S26.010)
Notice bibliographique
Résumé
Objective: GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27-month, global, Phase III, randomized, placebo-controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia). Background: Gantenerumab is a subcutaneous fully-human monoclonal antibody that binds to aggregated amyloid-beta species, including oligomers, fibrils, and plaques. Design/Methods: Eligible participants (50–90 years) with early AD were randomized 1:1 to receive subcutaneous gantenerumab or placebo, administered at the study site or at home. A universal titration scheme for all participants receiving gantenerumab, irrespective of apolipoprotein E ɛ4 (APOEɛ4) genotype, allowed participants to reach a target dose of 510 mg gantenerumab every 2 weeks. This titration maximizes gantenerumab exposure while balancing amyloid removal and amyloid-related imaging abnormalities (ARIA) risk for all individuals. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR-SB; higher scores indicate greater impairment). Secondary confirmatory and exploratory efficacy endpoints, tau and amyloid positron emission tomography, cerebrospinal fluid and plasma biomarkers, were also assessed. Results: GRADUATE I and II enrolled 985 and 980 participants, respectively. Change from baseline in CDR-SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference −0.31; 95% CI −0.66 to 0.05) and 2.82 and 3.01 in GRADUATE II (difference −0.19; 95% CI −0.55 to 0.17). The difference between gantenerumab and placebo groups in amyloid reduction at Week 116 was −66.57 (standard error [SE] 4.13) centiloids for GRADUATE I and −56.52 (SE 3.96) centiloids for GRADUATE II. ARIA-edema (ARIA-E) occurred with gantenerumab; ARIA-E were manageable and mostly asymptomatic. Conclusions: Gantenerumab did not slow decline in participants with early AD. Clinical benefit may require sufficient amyloid plaque removal; however, the parameters remain to be defined. Disclosure: Dr. Smith has received personal compensation for serving as an employee of Roche Products Ltd. Dr. Smith has stock in Hoffman La Roche. An immediate family member of Prof. Donohue has received personal compensation for serving as an employee of Janssen. Prof. Donohue has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Prof. Donohue has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. An immediate family member of Prof. Donohue has stock in Janssen. The institution of Prof. Donohue has received research support from NIH. Dr. Gruendl has received personal compensation for serving as an employee of F. Hoffmann-La Roche AG. Dr. Gruendl has stock in F. Hoffmann-La Roche AG. Dr. Grimmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AbbVie, Alector, Anavex, Biogen, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon. Dr. Grimmer has received personal compensation in the range of $500-$4,999 for serving as a lecturer with Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, and Schwabe. Dr. Perry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Perry has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. Dr. Perry has received personal compensation in the range of $0-$499 for serving as a Consultant for Eli Lilly. Dr. Perry has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Black has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. Dr. Black has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Black has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Dr. Black has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Black has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Black has received research support from Hoffmann-La Roche. The institution of Dr. Black has received research support from Biogen. The institution of Dr. Black has received research support from GE Healthcare. The institution of Dr. Black has received research support from Eli Lilly. The institution of Dr. Black has received research support from Genentech. The institution of Dr. Black has received research support from NovoNordisk. The institution of Dr. Black has received research support from UCB Biopharma. The institution of Dr. Black has received research support from Alkahest Inc. The institution of Dr. Black has received research support from University of Southern California - AHEAD 3-45 Study. Dr. Salloway has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EISAI. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lilly. Dr. Salloway has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for NovoNordisk. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Prothena. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. Dr. Salloway has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bolden. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. Salloway has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acumen. Dr. Salloway has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Marco Lyons has nothing to disclose. Dr. Rutten-Jacobs has received personal compensation for serving as an employee of F.Hoffmann-La Roche Ltd.. Dr. Rutten-Jacobs has stock in F.Hoffmann-La Roche Ltd.. Tobias Bittner has received personal compensation for serving as an employee of F.Hoffmann-LaRoche. Tobias Bittner has stock in F.Hoffmann-LaRoche. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen, Axon, JOMDD, Roche, Siemens. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis, Julius Clinical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for MagQu. Mr. Pelentrides has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Frederik Barkhof has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Combinostics. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for IXICO. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Matteo Tonietto has received personal compensation for serving as an employee of Roche. Matteo Tonietto has stock in Roche. Monika Baudler has received personal compensation for serving as an employee of Roche. Monika Baudler has stock in Roche. Dr. Fontoura has received personal compensation for serving as an employee of F. Hoffmann La Roche. Dr. Fontoura has received stock or an ownership interest from Roche Pharmaceuticals. Rachelle Doody has nothing to disclose.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,007 | 0,006 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,003 | 0,004 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,002 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,004 | 0,004 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,008 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».