Today, I review, link to, and excerpt from Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. JAMA. 2023 Aug 8;330(6):512-527. doi: 10.1001/jama.2023.13239.
All that follows is from the above resource.
AbstractImportance There are limited efficacious treatments for Alzheimer disease.
Objective To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.
Design, Setting, and Participants Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).
Interventions Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.
Main Outcomes and Measures The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.
MethodsTrial Conduct and OversightTRAILBLAZER-ALZ 2 was a 76-week, phase 3, randomized, double-blind, parallel, multicenter, placebo-controlled trial with participants screened at 277 sites in 8 countries (eTable 1 in Supplement 3). Enrollment began June 19, 2020, and ended November 5, 2021, and database lock/unblinding (double-blind phase) occurred on April 28, 2023. The trial was originally designed as a phase 2 trial but was subsequently amended to a larger phase 3 trial in February 2021 in an effort to confirm and expand the results of the previous TRAILBLAZER-ALZ trial. The trial was conducted according to the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice Guideline, and local regulatory requirements. An independent ethics committee/institutional review board at each site approved the study protocol (Supplement 1), which is provided alongside the statistical analysis plan (Supplement 2). Participants and study partners provided written consent. An independent data and safety monitoring board provided trial oversight.
Trial Design and ParticipantsThe trial included participants aged 60 to 85 years with early symptomatic Alzheimer disease (mild cognitive impairment [MCI]12 or Alzheimer disease with mild dementia).3 P-tau181 screening was removed in an early protocol amendment (eMethods in Supplement 3). Eligible participants had screening Mini-Mental State Examination (MMSE) scores of 20 to 28, amyloid pathology (≥37 Centiloids) assessed with 18F-florbetapir13 or 18F-florbetaben14 positron emission tomography (PET), and presence of tau pathology assessed by 18F-flortaucipir PET imaging with central image evaluation.13,15 Tau PET scans were categorized as low/medium or high tau by visual and quantitative reads as previously described16–20 (Supplements 1 and 2). Screening procedures also included magnetic resonance imaging (MRI), and key exclusion criteria included presence of amyloid-related imaging abnormalities of edema/effusion, more than 4 cerebral microhemorrhages, more than 1 area of superficial siderosis, and any intracerebral hemorrhage greater than 1 cm or severe white matter disease on MRI. For all eligibility criteria, see Supplement 1. Demographic information, including race and ethnicity, was collected to potentially understand any differences in disease course, treatment effects, or adverse events. The participants self-reported race and ethnicity based on fixed categories.
Randomization and InterventionEligible participants were randomly assigned in a 1:1 ratio (Figure 1) by a computer-generated sequence using interactive web response systems, with stratification by baseline tau categorization and enrolling sites; the randomization block size was 4. Randomized participants received either donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo, administered intravenously every 4 weeks for up to 72 weeks. If amyloid plaque level (assessed at 24 weeks and 52 weeks) was less than 11 Centiloids on any single PET scan or less than 25 but greater than or equal to 11 Centiloids on 2 consecutive PET scans (TRAILBLAZER-ALZ cutoffs9), donanemab was switched to placebo in a blinded procedure. Final adverse events and efficacy assessments were performed at 76 weeks. Amyloid-related imaging abnormality monitoring occurred with scheduled MRIs at 4, 12, 24, 52, and 76 weeks and unscheduled MRIs at investigator discretion. Any participant with detected amyloid-related imaging abnormalities had imaging every 4 to 6 weeks until resolution or stabilization. Amyloid-related imaging abnormality management and treatment interruption guidelines (eTable 2 in Supplement 3) depended on severity and symptoms. If infusions were held, investigators were advised to await resolution of amyloid-related imaging abnormalities of edema/effusion on radiographic imaging and stabilization of amyloid-related imaging abnormalities of microhemorrhages and hemosiderin deposits before resuming infusions. Permanent discontinuation was advised for macrohemorrhages. Investigators made final amyloid-related imaging abnormality management decisions.
OutcomesThe primary outcome was change in the iADRS score from baseline to 76 weeks in either the low/medium tau population or combined (low/medium and high tau) population. The iADRS is an integrated assessment of cognition and daily function from the 13-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog13) and Alzheimer Disease Cooperative Study—Instrumental Activities of Daily Living (ADCS-iADL), measuring global disease severity across the Alzheimer disease continuum as a single summary score. The iADRS is validated and captures clinical progression from MCI due to Alzheimer disease through moderate dementia due to Alzheimer disease, and treatment effects have been demonstrated across MCI and Alzheimer disease with mild dementia.6,9,21–27 The possible scores on the iADRS range from 0 to 144 (lower scores indicate greater impairment), and the meaningful within-patient change (MWPC) is a change of 5 points for those with Alzheimer disease with MCI and 9 points for those with Alzheimer disease with mild dementia. The MWPC, or minimal clinically important difference (MCID) as in Supplement 1 and 2, is a threshold for outcome scores (either patient-reported or physician-measured) above which a patient or physician would consider the change meaningful.28
Prespecified secondary outcomes included changes from baseline to 76 weeks by sum of boxes of the Clinical Dementia Rating Scale (CDR-SB), the ADAS-Cog13, the ADCS-iADL, and MMSE in the low/medium tau or combined population. Amyloid plaque reduction at 76 weeks, percentage of participants reaching amyloid clearance (<24.1 Centiloids measured by amyloid PET9,29) at 24 weeks and 76 weeks, tau PET1 (frontal cortical regions) change, volumetric MRI (vMRI; whole brain, hippocampus, and ventricles) change, and adverse events were additional secondary outcomes. Supplement 1 provides a complete listing and methodology of adverse events assessments. Amyloid-related imaging abnormalities of edema/effusion, amyloid-related imaging abnormalities of microhemorrhages and hemosiderin deposits, and infusion-related reactions were adverse events of special interest because they were considered class effects or observed in previous trials.9,30–32 Secondary outcomes related to pharmacokinetics and antidrug antibodies were also prespecified and are planned for subsequent studies. Exploratory outcomes included change in plasma P-tau217 (C2N Diagnostics) at 76 weeks and time-based analyses: progression risk using the CDR Global score (CDR-G; progression defined as any increase from baseline in CDR-G at consecutive visits), participants with no progression at 1 year on the CDR-SB, and clinical progression delay (ie, months saved with treatment) on the iADRS and CDR-SB. Additional information about outcome measures, including score ranges and MWPCs, is provided in eMethods in Supplement 3.
Prespecified primary and secondary outcomes were controlled for multiplicity (gated) at 76 weeks (Supplement 2 and eMethods in Supplement 3) except for MMSE, changes in vMRI measurements, and adverse event assessments. Additional time points were gated for amyloid clearance and P-tau217. Nominal P values are reported for gated and nongated outcomes.
DiscussionIn this phase 3 trial, donanemab significantly slowed Alzheimer disease progression, based on the iADRS score, compared with placebo in the low/medium tau and combined tau populations and across secondary clinical outcomes of CDR-SB, ADAS-Cog13, and ADCS-iADL scores.
Donanemab treatment resulted in clinically meaningful benefit (considered to be >20% slowing of clinical progression39–41) on the iADRS and CDR-SB scales for both the low/medium tau and combined populations, regardless of statistical model. Additional support for clinical relevance is the 38.6% risk reduction of disease progression as measured on the CDR-G score and the 4.4 to 7.5 months saved over the 18-month study (low/medium tau population). Furthermore, an estimated 47% of participants receiving donanemab had no change in the CDR-SB at 1 year (no disease progression), compared with 29% of participants receiving placebo.
This trial used a definition of a MWPC28 based on any incremental change on the CDR-G scale (Alzheimer disease with MCI to mild Alzheimer disease or mild Alzheimer disease to moderate Alzheimer disease) or point changes of −5 on the iADRS and 1 on the CDR-SB for those with Alzheimer disease with MCI or −9 on the iADRS and 2 on the CDR-SB for those with Alzheimer disease with mild dementia at consecutive visits from baseline. In analyses assessing whether individual participants reached thresholds of clinically important progression over the course of the trial, donanemab resulted in significantly lower risk of meaningful change on the CDR-G as well as the prespecified nongated analyses of the iADRS and CDR-SB outcomes.
The general belief is that treating Alzheimer disease at the earliest disease stage is likely to result in more clinically meaningful effects.43,44 Post hoc evaluation in only high tau participants demonstrated no differences (P< .05) on the primary outcome or on most secondary clinical outcomes in donanemab-treated compared with placebo-treated participants within the 18-month trial, with the exception of CDR-SB. Compared with significant differences in the low/medium tau population, this supports the hypothesis that a greater benefit from amyloid-lowering therapies may occur when initiated at an earlier disease stage.
ConclusionsAmong participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.
Back to topArticle InformationAccepted for Publication: June 28, 2023.
Published Online: July 17, 2023. doi:10.1001/jama.2023.13239
