Master Screening Study to Determine Individuals With Potential Trial Eligibility for Alzheimer's Disease Studies (NCT07177352)

Executive Summary

Executive Summary

The Master Screening Study (NCT07177352) represents a paradigm-shifting approach to Alzheimer's disease clinical trial enrollment conducted by Hoffmann-La Roche. This large-scale, longitudinal screening initiative is designed to identify and characterize individuals who may qualify for participation in multiple downstream Alzheimer's disease therapeutic trials. By implementing comprehensive biomarker and cognitive assessments at scale, Roche aims to create a more efficient and patient-centric clinical trial ecosystem that addresses one of the most significant challenges in Alzheimer's disease research: the recruitment of appropriately characterized participants who meet specific biological criteria for modern mechanism-directed trials["@rochescreening2024"].

Unlike traditional trial-specific screening approaches where each individual study conducts its own enrollment screening, this master screening protocol establishes a unified platform that can evaluate thousands of potential participants across diverse geographic locations. This approach recognizes that modern Alzheimer's disease trials require precise biological stratification based on amyloid positivity, tau pathology, and specific cognitive profiles—a level of characterization that traditional screening methods cannot efficiently achieve. The study leverages the growing availability of blood-based biomarkers, advanced PET imaging capabilities, and standardized cognitive assessments to build a comprehensive database of trial-ready participants["@battaglia2023"].

Trial Overview

Study Design and Objectives

NCT07177352 is structured as a Phase 3, multicenter, longitudinal observational study with the primary objective of establishing a large, well-characterized cohort of individuals who meet biomarker and cognitive criteria for participation in Alzheimer's disease clinical trials. The study employs a master protocol design that allows for flexible enrollment into multiple treatment arms as downstream therapeutic trials become available, creating an efficient platform for rapid patient recruitment[@cummings2024].

The master screening approach addresses several critical limitations in traditional clinical trial design. First, it reduces the redundancy of conducting separate screening assessments for each individual trial, which is both time-consuming and resource-intensive. Second, it allows participants to be characterized once and then matched to multiple potential trials based on their biological and cognitive profiles. Third, it enables the establishment of a pre-screened cohort that can be rapidly enrolled once a new therapeutic candidate enters clinical development, significantly accelerating the drug development timeline[@aisen2024].

Key Study Parameters

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT07177352 |
| Phase | Phase 3 |
| Status | Recruiting |
| Sponsor | Hoffmann-La Roche |
| Enrollment Target | 13,000 participants |
| Study Type | Observational / Screening |
| Start Date | July 2, 2025 |
| Anticipated Completion | July 31, 2035 |
| Duration | 10 years |
| Primary Outcome | Biomarker status and cognitive score classification |
| Study Design | Master protocol / Platform trial screening |

Scientific Rationale

Evolution of Alzheimer's Disease Clinical Trial Design

The landscape of Alzheimer's disease clinical trials has undergone a fundamental transformation over the past decade, moving from relatively broad inclusion criteria based primarily on clinical diagnosis toward highly specific biological criteria that require demonstration of both amyloid and tau pathology before enrollment. This shift reflects the growing recognition that Alzheimer's disease is biologically heterogeneous and that therapeutic agents targeting specific pathological mechanisms will only demonstrate efficacy in patients who possess the relevant target pathology[@jack2023].

Traditional clinical trial designs that enrolled patients based solely on clinical criteria—such as a diagnosis of mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease—often failed because a significant proportion of participants lacked the specific pathological target that the investigational therapy was designed to address. For example, anti-amyloid antibodies require participants to demonstrate elevated amyloid burden on PET imaging or in cerebrospinal fluid. Without this biological confirmation, trials may fail to detect therapeutic benefit simply because the enrolled population does not possess the target pathology[@sperling2019].

The master screening study addresses this challenge by establishing a large, pre-characterized cohort where participants have undergone comprehensive biomarker assessment including amyloid PET or CSF analysis, tau PET or CSF analysis, and detailed cognitive testing. This characterization enables precise matching between participants and trials, increasing the probability that enrolled participants possess the relevant pathological target while also enabling more efficient trial operations.

Biomarker-Based Patient Stratification

Modern Alzheimer's disease clinical trials employ multiple biomarkers to stratify participants into biologically homogeneous groups. These biomarkers fall into several categories that reflect different aspects of Alzheimer's disease pathology:

Amyloid Markers:

• Amyloid PET imaging (Florbetaben, Florbetapir, PiB)
• CSF Aβ42/40 ratio
• Plasma Aβ42/40 ratio and phosphorylated amyloid species

• Tau PET imaging (Flortaucipir)
• CSF total tau and phosphorylated tau (p-tau181, p-tau217, p-tau231)
• Plasma p-tau181, p-tau217, p-tau231

• CSF total tau
• MRI brain volume measurements
• FDG-PET hypometabolism patterns

• Comprehensive neuropsychological batteries
• Functional assessment scales
• Cognitive composite scores

Study Procedures

Participant Selection and Recruitment

The study employs a multi-modal recruitment strategy designed to reach a diverse population of individuals across the Alzheimer's disease continuum. Recruitment efforts target several key populations:

Cognitively Normal Individuals:

• Adults aged 50-90 years with normal cognitive function
• May have subjective cognitive concerns
• May possess biomarker evidence of preclinical Alzheimer's disease

• Cognitively normal individuals with biomarker evidence of amyloid pathology
• Represents a critical population for prevention trials
• May benefit most from early intervention[@van2021]

• Individuals with mild cognitive impairment attributable to Alzheimer's disease
• Positive amyloid and tau biomarkers
• CDR score typically 0.5

• Early-stage dementia with biomarker confirmation
• CDR score typically 0.5-1.0
• MMSE score typically 18-28

Comprehensive Assessment Battery

Participants undergo extensive baseline and follow-up assessments:

Cognitive Testing:

• Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
• Trail Making Test A and B
• Digit Symbol Substitution Test
• Category Fluency
• Rey Auditory Verbal Learning Test (RAVLT)
• Clinical Dementia Rating (CDR)
• Mini-Mental State Examination (MMSE)
• Montreal Cognitive Assessment (MoCA)

• Blood draw for plasma biomarker analysis (Aβ42/40, p-tau181, p-tau217, p-tau231)
• CSF collection via lumbar puncture (optional)
• Genetic apolipoprotein E (APOE) genotyping

• Amyloid PET (where available)
• Tau PET (where available)
• Structural MRI
• FDG-PET (selected sites)

• Detailed medical and neurological history
• Psychiatric evaluation
• Functional assessment
• Safety laboratories

Blood Biomarker Program

A distinctive feature of this master screening protocol is the extensive use of blood-based biomarkers for initial participant characterization. Recent advances in ultra-sensitive assay technologies have enabled reliable measurement of Alzheimer's disease biomarkers in blood samples, dramatically reducing the need for invasive procedures like lumbar punctures or expensive PET imaging for initial screening[@kumar2015].

The blood biomarker panel includes:

• Plasma Aβ42/40 ratio: Reduced ratio indicates brain amyloid positivity
• Plasma p-tau181: Elevated levels indicate Alzheimer's-type tau pathology
• Plasma p-tau217: Highly specific for Alzheimer's disease pathology
• Plasma p-tau231: Detects early tau changes in preclinical AD
• Neurofilament light chain (NfL): Marker of neurodegeneration

Clinical Trial Matching

Downstream Trial Types

Participants in the master screening study become eligible for enrollment in multiple downstream therapeutic trials based on their biomarker and cognitive profiles:

Anti-Amyloid Therapies:

• Monoclonal antibodies targeting various Aβ species
• Amyloid vaccination strategies
• BACE inhibitors (where applicable)
• Requires positive amyloid biomarker

• Tau immunotherapy (active and passive)
• Tau aggregation inhibitors
• Requires positive tau biomarker

• Synaptic protective agents
• Mitochondrial targeting compounds
• Anti-inflammatory strategies

• Broad mechanisms targeting multiple pathways
• Combination therapy approaches
• Prevention trials in preclinical populations

Registry Benefits

Participants benefit from the master screening design in several ways:

Participating Sites

The study is being conducted at multiple centers across the United States and internationally, with particular emphasis on regions with established research infrastructure and diverse patient populations:

United States Sites (Selected)

| Location | City | State |
|----------|------|-------|
| Banner Sun Health Research Institute | Sun City | Arizona |
| University of Arizona | Phoenix | Arizona |
| Cedars-Sinai Medical Center | Los Angeles | California |
| Stanford University | Palo Alto | California |
| University of California, Irvine | Irvine | California |
| University of Southern California | Los Angeles | California |
| Mayo Clinic | Jacksonville | Florida |
| University of Miami | Miami | Florida |
| Massachusetts General Hospital | Boston | Massachusetts |
| Brigham and Women's Hospital | Boston | Massachusetts |
| Columbia University | New York | New York |
| Mount Sinai School of Medicine | New York | New York |
| Cleveland Clinic | Cleveland | Ohio |
| University of Pennsylvania | Philadelphia | Pennsylvania |

International sites span North America, Europe, Australia, and Japan, creating a truly global screening network.

Outcomes and Significance

Primary Outcome Measures

The primary outcomes of the master screening study are:

Secondary Outcomes

Secondary endpoints include:

• Correlation between blood biomarkers and PET/CSF biomarkers
• Rate of biomarker progression in longitudinal follow-up
• Cognitive decline rates across different biological subgroups
• Diversity and representativeness of the screened cohort

Impact on Drug Development

The master screening model has the potential to significantly accelerate Alzheimer's disease drug development:

Reduced Screening Failures: By pre-characterizing participants, downstream trials can expect higher screening success rates, reducing the time and cost associated with screen failures.

Faster Enrollment: Ready access to a pre-screened cohort enables rapid enrollment once a new trial opens, critical for maintaining competitive timelines.

Enhanced Trial Power: More precise biological stratification may enable smaller, more efficient trials while maintaining statistical power.

Patient Centricity: Participants benefit from reduced burden of repeated screening procedures and faster access to investigational therapies.

Future Directions

Platform Trial Integration

As the master screening study matures, it is expected to integrate with platform trial designs that evaluate multiple therapeutic candidates simultaneously within a single operational framework. This approach, already successful in oncology, enables efficient comparison of different mechanisms and rapid graduation of promising therapies to later-stage development[@cummings2024].

Precision Medicine Implementation

The comprehensive biomarker data generated by this study will contribute to the development of precision medicine approaches in Alzheimer's disease. By understanding the relationships between biomarkers, cognitive outcomes, and treatment responses across large populations, researchers can develop algorithms to predict optimal treatment selection for individual patients based on their biological profiles.

Registry and Natural History

The long duration of the study (10 years) enables collection of valuable natural history data on biomarker and cognitive progression across the Alzheimer's disease continuum. This data will inform future trial design, identify optimal outcome measures, and enhance understanding of disease progression.

Cross-References

Related Pages

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Amyloid Beta](/proteins/amyloid-beta)
• [Tau Protein](/proteins/tau)
• [p-Tau Biomarkers](/mechanisms/taupathology-biomarkers)
• [Clinical Trials Overview](/clinical-trials/overview)
• [Drug Development Pipeline](/clinical-trials/drug-pipeline)
• [Preclinical Alzheimer's Disease](/mechanisms/preclinical-ad)
• [Biomarker Assessment](/mechanisms/biomarker-assessment)

External Resources

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT07177352)
• [Roche Alzheimer's Disease Pipeline](https://www.roche.com/research_and_development/pipeline)
• [Alzheimer's Association TrialMatch](https://www.alz.org/trials)

References