The clinical trial design has been described previously [13]. Primary endpoints were the onset of MCI due to AD [10] or AD dementia [14] as adjudicated by a committee. Study visits were conducted every 6 months over a period of approximately 4 years, with anticipated study completion when 202 events would be observed in the efficacy population.
Enrollment began 1 August 2013 and was completed 21 December 2015; in total, 57 clinical sites were included from the USA, the UK, Australia, Switzerland, and Germany. While the trial originally was designed to enroll approximately 5400 participants to accrue 410 endpoint events, the protocol was modified, and this increased the expected effect size from 30% to 40%, while the number of enrolled participants was reduced to 3494. The study was terminated early by the sponsor in January 2018 for not meeting the futility analysis criteria. The trial results are reported elsewhere [15].
Clinical assessments
The two types of study visit after baseline were: (1) an in-clinic visit scheduled at 6‑month intervals and (2) a comprehensive medical follow-up visit (CMFV) that occurred usually within 30 days after a participant met protocol-specified trigger criteria at the regular 6-month visit. The assessments collected at these visits are listed in Fig. 1. The 6-month visits were intended to evaluate safety and to assess clinical and neuropsychological function, using information obtained from the participant and their study partner. The CMFV required additional assessments to aid the site investigator’s clinical diagnosis when a 6-monthly interval visit suggested a change in a participant’s cognitive status. After each CMFV, the investigator assigned a provisional clinical diagnosis to the participant’s case from the following six categories: cognitively normal; reversible cognitive impairment (e.g., from a medical condition or medication); irreversible cognitive impairment (e.g., from a medical condition such as a stroke or tumor); MCI due to AD; AD dementia; or non-AD dementia. Following a CMFV, participants continued regular 6-monthly visits unless a site investigator decided to withdraw the participant from the trial or an adjudication decision determined that the participant met the criteria for a primary endpoint.
Initiation of case adjudication
Fig. 2 summarizes the protocol-defined criteria that would initiate adjudication of a case. The first criterion was a determination that a participant met CMFV trigger criteria, that is, suspicion of cognitive decline, at two consecutive study visits. The second criterion required an MCI due to AD diagnosis by an investigator after any CMFV. In these situations, the participant continues in the trial and returns for the next 6-month interval visit. This visit would require a CMFV regardless of whether the trigger criteria were met so that the adjudication review would have data from two consecutive visits upon which to base a decision regarding the primary endpoint event. The third criterion was an investigator’s diagnosis of AD dementia, non-AD dementia, or irreversible cognitive impairment. Each of these diagnoses presented the possibility that a participant had declined to AD dementia, which was also a primary endpoint event. Therefore, these cases were assigned for adjudication after the CMFV when the diagnosis was made.
Cases meeting these adjudication initiation criteria were prepared for adjudication review by a vendor company (IQVIA, Research Triangle Park, NC, USA), using an electronic platform (Merge eClinical Operating System) to create a dossier that included clinical profile information (e.g., demographics, cognitive battery profile sheets, and noncognitive assessment summaries), investigator clinical narratives, visit source worksheets, Clinical Dementia Rating (CDR) scale worksheets, Clinical Global Impression of Change source documents, laboratory reports for values reported as adverse events, and brain imaging scans and reports (if applicable). To provide robust and consistent case details, the study team implemented guidance for site investigators regarding their clinical narratives by standardizing a Clinical Assessment Form (CAF) to be included with each dossier. The CAF narrative was required for any clinical diagnosis other than “cognitively normal” and provided a description of disease onset (e.g., “abrupt” or “insidious”) and disease course (e.g., slowly progressive versus stepwise), a neurocognitive profile (neuropsychologist report), a summary of other clinical data, and comments on any complicating medical factors.
CIAC composition and remit
The Cognitive Impairment Adjudication Committee (CIAC) comprised seven independent experts. One served as chair and had responsibility for committee oversight and ensuring endpoint event harmonization, that is, the appropriate and consistent application of MCI due to AD and AD dementia diagnostic criteria in endpoint event decisions across sites. Six served as reviewing members, with two each having expertise in neurology, psychiatry, and clinical neuropsychology. Members did not otherwise participate in the conduct of the trial.
A stratified random assignment method was used to assign each dossier to a three‑member review panel, with one expert each in neurology, psychiatry, and neuropsychology (Fig. 3). Eight different combinations of reviewing members were randomly assigned dossiers in this manner.
The committee’s remit was to review data within the Merge web-based study portal for participants suspected of cognitive decline and to provide a primary endpoint event outcome decision on whether or not the participants met criteria for MCI due to AD or AD dementia. According to the study protocol, “MCI due to AD” was recorded when a participant met core clinical criteria for MCI due to AD at two consecutive study visits and CMFVs, and “AD dementia” was recorded when a participant met the NIA/AA criteria at any single study visit and CMFV [14].
Adjudication procedures
The method for adjudication adapted from Gabel et al. (2010) [16] was: (1) the presentation of a uniform set of information to the review panel; (2) an initial independent decision from each reviewer, which is recorded and subsequently shared with the other reviewers; (3) discussion by the reviewers of their opinions; and (4) a final group decision requiring consensus. Adjudicators were blinded to the risk and treatment strata of participants whose cases were to be adjudicated [16].
After a case was assigned, the process could progress through up to three stages; the required unanimous agreement could occur at any of these stages (Fig. 4). Initially (stage 1), the three members independently reviewed each dossier and logged their event decision within 14 days. If the three reviewers reached the same decision, the dossier and reviews were sent to the chair. If the chair ratified the decision, the decision was shared with the investigator. If the chair did not agree with the decision, the dossier would be reviewed by all committee members at a monthly teleconference. Stage 2 of the process was initiated if agreement was not reached after the independent review; the three reviewers shared each other’s comments and decisions, and each had an additional 7 days to reevaluate their own decision. Agreement at the end of this stage resulted in the same procedures that were followed at stage 1, but if unanimity was still not reached, or if the chair did not ratify the decision, the dossier was reviewed at the next monthly teleconference (stage 3) by all committee members. This meeting could not adjourn until unanimity was reached on the endpoint decision. If agreement could still not be reached, the chair was empowered to cast the deciding vote.
While the adjudication committee’s endpoint decision determined the participant’s disposition, the site investigator’s clinical diagnosis was expected to guide decisions regarding clinical management because a site investigator is ultimately responsible for a research participant’s care and well-being. During the adjudication process, committee members could make requests for additional information, which were conveyed through the vendor.