Clinical trials are carefully designed research studies that test new treatments, interventions, or diagnostic methods in humans. They are broadly classified as interventional trials, where researchers introduce an intervention and observe its effects, or observational trials where researchers observe participants without intervention.

Additionally, randomized controlled trials (RCTs) are considered the “gold standard” in clinical research. Participants are randomly assigned to one or more groups (i.e., experimental treatment vs. control group(s) receiving standard treatment or placebo). The placebo helps determine if the observed effects are truly due to the treatment, and the overall randomization helps minimize bias and ensures that treatment groups are comparable. Trials can be designed as single-blind (only researchers know the treatment assignments) or double-blind (neither participants or researchers know), further reducing bias in observing and interpreting results.

For a more detailed overview of the elements of clinical trials, take a look at this recent publication. Beyond this broad categorization, clinical trials can be further defined by their purpose and design.

Based on Purpose:

Prevention Trials: Investigate whether a treatment (like a vaccine, medicine, or lifestyle change) can prevent a disease from occurring or recurring.
Detection/Screening Trials: Aim to find better ways to detect diseases or health conditions earlier, before symptoms appear.
Treatment Trials: Evaluate new drugs, drug combinations, medical or surgical procedures, or other therapies and devices for treating a specific disease.
Diagnostic Trials: Focus on advancing diagnostic methods by developing and implementing new tests or procedures.

Based on Design:

Single-Drug Clinical Trial (also called N-of-1 trial or single-subject trial): This unique trial design tailors treatment to an individual patient by systematically comparing multiple interventions over time—often using crossover methods—to identify the most effective option for that specific patient. While not generalizable to a population, they are useful for advancing precision medicine, particularly for chronic conditions or extremely rare genetic disorders.
Umbrella Trial: An umbrella trial targets a single disease but divides patients into distinct subgroups based on specific genetic mutations or biomarkers, with each subgroup receiving a tailored treatment. This design enables the simultaneous evaluation of multiple therapies within the same trial, leveraging a shared control group and centralized infrastructure. By streamlining resources and accelerating data collection, umbrella trials make drug development more efficient.
Basket Trial: In contrast to umbrella trials, basket trials evaluate the effectiveness of a single drug across multiple disease types. All patients receive the same treatment targeting a shared characteristic or mechanism of action. By testing one drug across various diseases simultaneously, basket trials reduce redundant studies, streamline patient recruitment, and optimize the use of trial infrastructure and resources.
Platform Trial: This is a highly adaptive and efficient trial design that allows multiple treatments for a disease or condition to be tested and compared within a single study. A key advantage is the ability to add or drop treatment arms during the trial based on pre-established rules and emerging data. Platform trials typically use a shared control group, enable continuous patient enrollment, and apply statistical methods that continuously evaluate new and existing therapies. By eliminating the need to start separate trials for each new treatment, this approach streamlines research, saves resources, and accelerates drug development.

Traditionally, tauopathy trials have followed a straightforward treatment design which tests a single drug in a single disease. However, due to the heterogeneity of tauopathies, the plethora of active trials, and the lack of approved therapies, researchers have increasingly explored alternative trial designs to address these challenges. Below, we highlight three examples of innovative clinical trials that have adopted new design strategies to advance research and better serve the tauopathy community.

Case Report #1: Alzheimer’s Tau Platform

The Alzheimer’s Tau Platform (ATP) is a Phase 2 clinical trial designed to evaluate combination therapies for early Alzheimer’s disease (AD). Interventions in the early stages of AD have the greatest potential to slow or halt its progression. The rationale for this approach stems from our understanding of AD pathology, which involves two primary protein aggregates—amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. We know that Aβ accumulation often initiates the disease, whereas tau pathology is more closely aligned with neurodegeneration and cognitive decline. Therefore, a dual-targeting strategy is hypothesized to be more effective than monotherapy.

As a Phase 2 trial, ATP will focus on assessing the safety, tolerability, and preliminary efficacy of a combination of amyloid-reducing and tau-targeting agents in participants who are in the early stages of AD, such as those with mild cognitive impairment due to AD or mild AD dementia. The platform design enables the simultaneous or sequential evaluation of multiple tau-directed therapies, often in combination with an anti-amyloid agent. By sharing control groups and trial infrastructure, this efficient approach can significantly accelerate drug development. A successful ATP trial could generate critical data to advance combination treatments into larger, more definitive Phase 3 studies—offering renewed hope for more impactful treatments for early AD.

Case Report #2: TauBasket

The TauBasket trial was the first basket trial for neurodegenerative diseases that investigated the effectiveness of the drug TPI-287, a microtubule-stabilizing molecule, in treating toxic tau protein buildup across three different tauopathies (NCT01966666 and NCT02133846)—AD, corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). This innovative trial design aimed to evaluate a single drug against a shared underlying pathology, rather than individual diagnoses. While TPI-287 ultimately did not show promise in treating any of these diseases, the study yielded valuable insights. Notably, TPI-287 caused allergic reactions in AD participants but not in those with CBS or PSP, suggesting that even with a shared tau pathology, treatment responses can vary due to underlying differences in disease mechanisms or patient characteristics.

The primary takeaway from the TauBasket trial was the successful demonstration of the basket trial methodology in tauopathies. This approach allows efficient testing of drugs targeting common pathological mechanisms across various diseases, potentially accelerating drug development by identifying which patient populations are most likely to benefit. While TPI-287 itself was not effective, the trial established a helpful framework for future research into tau-targeted therapies, paving the way for more refined treatment strategies for neurodegenerative diseases.

Case Report #3: Progressive Supranuclear Palsy Trial Platform (PTP)

The University of California, San Francisco (UCSF) has recently announced a groundbreaking new PSP platform trial. This Phase 2 trial aims to employ an adaptive design, allowing for the simultaneous evaluation of multiple experimental therapies against a single placebo group. Patients participating in the PTP trial have a higher chance of receiving an active drug, with a 3:1 randomization ratio. After 12 months, all participants will have the opportunity to receive an active treatment in an optional open-label extension phase. The trial is expected to begin enrollment in late 2025, focusing on individuals with Richardson’s syndrome, the most common subtype of PSP. The overarching goal is to determine the safety, tolerability, and clinical proof of concept for the tested therapies.

At the 2025 Tau Global conference, two promising drug candidates were selected for evaluation: AADvac1 by Axon Neuroscience and AZP2006 by Alzprotect. AADvac1 is an active immunotherapy that targets pathological tau proteins—central to PSP pathology—by eliciting antibodies to prevent tau aggregation and spread. AZP2006 is a small molecule designed to restore lysosomal function and modulate progranulin, thereby reducing tau aggregation and neuroinflammation. Additional compounds are expected to be announced for inclusion in the platform trial later this year.

This collaborative public-private partnership represents a significant step forward in addressing the urgent unmet needs of PSP patients and their families. By establishing a perpetual infrastructure for evaluating PSP therapies, the platform trial offers new promise for accelerating the development of effective treatments and ultimately improving the lives of those impacted by this devastating disease.

The complex challenges of tauopathies— from diverse patient populations and elusive biomarkers to rapid disease progression—demand a shift from traditional trial methods. Adaptive designs, platform trials, and master protocols enable greater efficiency, flexibility, and simultaneous evaluation of multiple therapies. The ultimate goal is to accelerate the discovery of treatments that can halt or even reverse disease progression. Through collaboration, data sharing, and continual refinement, we can transform the landscape of tauopathy research, offering tangible hope and progress to patients and families.

Though the journey is long, each meticulously designed trial brings us closer to a future free of these devastating diseases.