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ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world.

Explore 497,586 research studies in all 50 states and in 222 countries..

ClinicalTrials.gov is a resource provided by the U.S. National Library of Medicine.

IMPORTANT : Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

Before participating in a study, talk to your health care provider and learn about the risks and potential benefits .

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Velocity is the world's leading integrated site organization.

Sponsors and cros trust velocity to deliver high-quality clinical trial data and patient care with unprecedented efficiency., simplify everything from site selection to study close-out.

Velocity unifies operational processes to provide world-class sites, reliable enrollment, and predictably high performance for your trials.

The right sites. The right investigators. The right partner for you.

Strategically located to give you access to diverse specialty populations, Velocity's sites are supported by next-gen technologies and patient engagement capabilities. Welcome to recruitment and retention reimagined.

Scale for a purpose: Supporting research programs worldwide

From the leading pharma companies, to the most pioneering biotech startups, Velocity supports those who are exploring new frontiers in human health.

Whether you’re ready to conduct a single-site study or a complex, high-volume clinical trial, contact Velocity.

VISION Achieves 2,000 Patient Randomizations

Just one year ago, VISION technology empowered its first patient to self-screen and self-schedule a visit for a clinical trial at Velocity. In March, we announced that VISION had contributed … Read more

Video: Participant Advisory Committee Meeting Insights

We can talk about elevating the patient’s voice in clinical research, or we can listen. So let’s listen! In this clip, you’ll hear from both current and past clinical trial … Read more

Jerome Adams, MD, MPH, Provides Internal Presentation About the Importance of Diversity in Clinical Trial Inclusion

On May 30, Velocity welcomed former Surgeon General Jerome Adams, MD, MPH, to an internal presentation about the importance and direction of diversity in clinical trial inclusion, followed by a … Read more

Raghu Punnamraju, Velocity CTO, On AI in Clinical Research

Velocity is using multimodal LLMs, like OpenAI’s GPT-4o and others, to enhance productivity. At the forefront of this shift is Raghu Punnamraju, Velocity’s Chief Technology Officer. In this article he shares … Read more

Quality. Continuity. Velocity.

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COVID-19 Research Studies

More information, about clinical center, clinical trials and you, participate in a study, referring a patient.

About Clinical Research

Research participants are partners in discovery at the NIH Clinical Center, the largest research hospital in America. Clinical research is medical research involving people The Clinical Center provides hope through pioneering clinical research to improve human health. We rapidly translate scientific observations and laboratory discoveries into new ways to diagnose, treat and prevent disease. More than 500,000 people from around the world have participated in clinical research since the hospital opened in 1953. We do not charge patients for participation and treatment in clinical studies at NIH. In certain emergency circumstances, you may qualify for help with travel and other expenses Read more , to see if clinical studies are for you.

Medical Information Disclaimer

Emailed inquires/requests.

Email sent to the National Institutes of Health Clinical Center may be forwarded to appropriate NIH or outside experts for response. We do not collect your name and e-mail address for any purpose other than to respond to your query. Nevertheless, email is not necessarily secure against interception. This statement applies to NIH Clinical Center Studies website. For additional inquiries regarding studies at the National Institutes of Health, please call the Office of Patient Recruitment at 1-800-411-1222

Find NIH Clinical Center Trials

The National Institutes of Health (NIH) Clinical Center Search the Studies site is a registry of publicly supported clinical studies conducted mostly in Bethesda, MD.

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Download white papers created by the Society for Clinical Research Sites (SCRS), which share valuable insights into critical topics for research site sustainability and stronger industry partnerships. These industry-leading white papers provide timely information that can inform and empower decision-making for more collaborative and efficient clinical research.

2023 Site Landscape Survey White Paper

The SCRS Site Landscape Survey shows a comprehensive look at what’s impacting site success from year to year and the impact on the broader life sciences industry. Reflecting the current pulse of the industry, this year’s survey shares insights related to clinical technology and innovation, participant diversity and inclusion, site financial health, and record retention. This report serves as a tool for sites and industry organizations to optimize their approaches to trial design and implementation for more productive, effective, and efficient studies.

Workforce Challenges at Clinical Research Sites

Since the COVID-19 pandemic began, changing macro- and micro-economic factors have impacted all industries, and clinical research is no different. With unprecedented workforce challenges and increasing costs, clinical research sites are struggling to recruit and retain qualified staff. SCRS conducted a global survey to explore the current workforce challenges at clinical research sites and understand the impact they are having on the clinical research industry. 

2022 Site Landscape Survey

For the 10th consecutive year, SCRS conducted an annual survey to gather data about the current state of operational health at clinical research sites. The survey responses help us understand factors that are impacting sites’ success and longevity, and provide helpful insights for the life sciences industry to optimize clinical research productivity. The results offer useful insights into the evolution of clinical research from the perspective of sites, as well as a better understanding of factors that impact their operations and sustainability. This. year's survey includes data on site finances, workforce considerations, and larger trends such as decentralization and digitalization.

Site Perspectives on Decentralized Clinical Trials

While decentralized clinical trial (DCT) technologies have enabled patients and sites to participate in novel and innovative ways, there is a lack of qualitative and quantitative data from sites on their use and implementation. Medidata collaborated with SCRS to survey sites on DCT topics, aiming to gauge the impact on sites for aspects such as scope, effectiveness, and enablement. Insights into sites' experiences with DCTs will aid stakeholders in refining trial design, operations, and regulatory policies for enhanced patient and site service and global health outcomes.

2021 Site Landscape Survey

In the 2021 Site Landscape Survey, nearly 600 respondents from various roles and organizations shared insights on their operations, partnerships, finances, and experiences with technology. The results, while reflecting patterns from previous surveys, also highlight the impact of the ongoing global pandemic and newer trends in clinical research. The data underscores the effects of digitalization and globalization on clinical research sites, revealing varied outcomes such as increased revenue or declined study opportunities. Ongoing trends, like the adoption of eClinical technologies, continue to influence operational strategies. The survey offers actionable insights to enhance relationships and optimize operational health, contributing to improved collective success in clinical development.

A Pilot Study to Examine the Validity and Reliability of a Site Assessment Checklist for the Evaluation of Best Practices in Recruiting Diverse Patient Populations for Clinical Trials

Recognizing the crucial role of diverse patient populations in clinical trials, stakeholders in pharmaceutical development emphasize the need for inclusive recruitment. From this need, SCRS established a program to increase education on inclusive recruitment opportunities. The initiative also developed a 27-item checklist evaluating sites' knowledge for recruiting diverse patients for clinical trials. The checklist serves as a self-assessment tool for sites, aiding them in developing improvement action plans. This paper discusses the development and psychometric testing of the diversity assessment tool, highlighting efforts to enhance best practices in recruiting diverse patient populations for clinical trials.

Patient Centricity and Virtualizing Technologies in a COVID-19 World

How sites view the digital tools that encourage patient centricity is critically important to clinical trial stakeholders during the COVID-19 era, as decentralized trials are destined to play a larger role.  To gauge sites’ level of acceptance and knowledge about virtualizing technologies, SCRS. collaborated with Medidata to conduct an online survey.  It took place between May 19 and July 10, 2020, a meaningful timeframe as the pandemic was well underway, allowing sites to respond to questions through a “COVID lens”. The survey measured current and anticipated levels of adoption of patient-centric tools, along with the sites’ perspective on patient reactions.

Sites Speak Out on Clinical Trial Technology Overload

SCRS collaborated with IQVIA to conduct a global site-based survey focused on the expanding volume of clinical trial technologies. The survey aimed to pinpoint the burdens sites face in adopting an array of new systems, each with its own passwords and required training. The survey was conducted on the cusp of the COVID-19 pandemic, and with sponsors embracing virtual clinical trials, sites and patients will be able to remain safer by decreasing the number of visits, replacing site visits with virtual visits, and increasing remote monitoring.

Impact Assessment of Decentralized Clinical Trials (DCT) Awareness in the Clinical Research Industry

Decentralized Clinical Trials (DCTs) have the potential to provide tremendous efficiencies to the clinical trial process. However, understanding the great impact they are having on sites and the trial industry is critical to taking the appropriate steps towards implementation. In collaboration with VirTrial, SCRS embarked on a survey and publication initiative to provide this important analysis. Primary concerns and the current state of needs at the site level are centered around assuring patient safety and adequate education and understanding. This white paper expands on the value of DCTs and what needs to be done in order to prepare for them.

Impact Assessment of eClinical Technologies and Industry Initiatives on Sites

Sponsors and CROs fight a continuous uphill battle to reduce complexity, streamline business processes and workflows, ensure compliance and increase efficiencies in the pursuit of bringing drugs to market. Fundamental to this goal is a site-centric approach to conducting clinical trials. Sites are dynamic environments, and new technology and industry initiatives are important complements to the critical need for relationship-building and maintenance. But, are these technologies and initiatives helping improve site and sponsor-CRO collaboration and creating a competitive edge through improved clinical trial performance? To explore these issues and their impact, SCRS and Oracle Health Sciences surveyed clinical research site professionals around the world.

Financial Barriers to Site Sustainability, Patient Experience and Overall Trial Success

It is well-known and frequently documented that financial stress is one of the primary issues negatively impacting clinical research site success. Previous data collected by SCRS, in partnership with Greenphire, identified four major challenges affecting clinical trial success:  limited operating cash, manual invoicing processes, untimely payment frequency and lack of financial transparency are all top of mind for sites globally. However, it is important to understand that the barriers to success are not exclusively correlated to site payments. In fact, the challenges are evident throughout the life-cycle of a clinical study, as early as the study budget negotiation processes and all the way through patient engagement and payments.

Recruiting Diverse Patient Populations in Clinical Studies: Factors That Drive Site Success

As part of its Diversity Awareness Program, SCRS conducted a pilot study and survey to determine how successfully sites recruit diverse patient populations for clinical studies and to examine the factors that drive site success or lack thereof. This is the first known comprehensive study of the extent to which sites report being successful in recruiting diverse patient populations in their clinical studies and the factors related to this success. This data may help pave the way for the development of strategies sites can use to enhance their ability to recruit diverse patient populations in clinical studies.

Patient Diversity Awareness: Developing a Better Understanding of the Knowledge, Expertise, and Best Practices at Clinical Research Sites to Meet the Needs of an Increasingly Diverse United States Population

The FDA has imposed, and continually is tightening the reigns on ensuring that clinical trials enroll racially/ethnically diverse patients. This warrants bolstered safety and efficacy for the representative patient population that will be using new medical products. Sponsors are highly encouraged to obtain a diversified patient population on all trials, not just for particular therapeutic indications. In this pilot study, site interviews were implemented to identify factors that affect the enrollment of diverse patient populations in clinical research trials. Future efforts to increase site awareness and best practices for inclusion of diverse patient populations in clinical research must therefore target issues that matter most to sites and patients to benefit society overall resulting in increased patient diversity within clinical trials.

Site Budget Development and Payment Systems: A Call for Transparency from Clinical Research Sites

SCRS research outlines the role technology innovations have on the power to bring transparency and efficiency to the site payment and budget process, however, legacy processes and practices fail to embrace these solutions. This white paper explores potential solutions and reports on site responses identifying features they would find to be the most valuable, providing a potential road map for industry partners to use in addressing these concerns.

Why Is Clinical Source Data Still Collected on Paper?

This white paper builds on data from the Research Site Source Survey, reporting that paper source document creation is a task completed at many sites at significant expense and risk to quality. This task continues despite widespread adoption of electronic medical records and the development of a regulatory framework for eSource. In this paper, the task of paper source document creation and transcription is explored and the total cost calculated.

Site Payments and Patient Reimbursements: A Global Perspective

This white paper presents global data on site perspectives on payments and patient reimbursement. The white paper validates SCRS advocacy for key improvement from payers. It also demonstrates a complex relationship between payment processes to sites and patient payments, linking these key improvements to the patient experience.

Meeting Clinical Trial Site Needs with Patient Recruitment Agency Services White Paper

Innovation in how patients and clinical trials are brought together is urgently needed. Recruitment that takes longer than expected increases the costs of products and prevents new products from being brought to market. Too many studies are canceled because recruitment is never completed. This white paper presents information collected from clinical research sites in the US and five European countries and provides new insights into factors holding back patient recruitment innovation and how they can be overcome.

CLEAR (Common Language Evaluation and Reconciliation) White Paper

The purpose of Common Language Evaluation and Reconciliation (CLEAR) is to streamline contract negotiations and thereby accelerate site initiations, leading to increased recruitment timeliness and reduced study start-up costs. Improving productivity by reducing cycle times and accelerating clinical research will allow industry to get new treatments in development to patients faster without sacrificing quality. This initiative benefits all the stakeholders within industry — sponsors, CROs, and sites — but most importantly patients.

Site Study Dashboard White Paper

What if sponsors had a standardized process for sharing information about sites in the form of a Site Study Dashboard? Sponsors have this information readily available. Sites want a dashboard that reflects their performance. This paper lays out nine key metrics that can be shared with sites and the methodology of how the data can be shared to enhance the relationship with the site. It also provides insight into the format of data that sites are most likely to find meaningful.

Site Payment White Paper

This paper documents five burdens the current site payment structure places on sites and solutions to address these issues. Additionally, the paper outlines further burdens that will be examined over 2016-2017 by the SCRS payment initiative working group.

The Approach of Protocol Training on Clinical Trial Quality White Paper

In an era of increasing protocol complexity, growing Investigator complaints and inspections, higher Investigator turnover and the focus on quality by design, it is becoming more important than ever to ensure investigative sites are adequately trained to deliver high-quality data. The growing number of FDA findings related to failure to follow the investigational plan should be a call to action for sponsors, CROs and investigative sites alike to pursue a quest for “zero defects.” Whether this trend is related to increased protocol complexity, the higher number of less experienced Investigators participating in clinical trials, the protocol training approach or some other combination of factors, it demands action.

The Quest for Site Quality and Sustainability White Paper

There are a plethora of industry initiatives focused on enhancing the quality of clinical trials. And much of the focus is on defining site quality and performance metrics from the industry perspective. In this quest for site quality and sustainability,  SCRS recognized that a key perspective was missing: that of investigative sites. How do the sites view their current levels of quality? How do they feel they can and should be measured? What do they need to do internally to improve their performance and what do they need from their sponsor and CRO partners to enhance their quality as well as sustainability?

Responsible Site Management White Paper

These Best Site Practices are meant to provide clarity and guidance to sites to promote the achievement of a compliant, efficient and sustainable research site, and to be recognized as a site of commitment and quality by the research enterprise. It covers qualifications for Principal Investigators and site staff, how to gauge site performance and set up site infrastructure, remaining compliant with regulatory agencies, and more.

An Industry in Crisis White Paper

This paper examines the acute challenges faced by investigators and clinical research sites within the life sciences enterprise. As the sustainability of many sites has become increasingly tenuous, established sites and investigators struggle to remain viable. Others enter the industry with little chance to succeed, often quickly departing after conducting only one study, or no studies at all. There are enormous societal costs associated with this crisis, including financial costs to industry – and most importantly – the human cost of productive lives lost. SCRS shares emerging solutions that will better integrate clinical sites and investigators as full and sustainable partners within the clinical research ecosystem.

Better Payment Terms for Sites White Paper

A new medical therapy has just been approved and the sponsor touts this major achievement by publicizing the clinical trial results and the number of subjects who participated in the pivotal studies. Whether that number is 300 or 3,000, those subjects had to be recruited, enrolled, randomized, and engaged in a series of protocol-related visits to investigative sites, the very backbone of the clinical trials industry. Without sites, it would be virtually impossible to conduct clinical research. And whether those sites are free standing, linked to a medical practice or part of an academic medical center, they are a precious resource. Yet many are struggling, not only with ever more complex protocols, but also with the financial realities of operating a clinical research site.

Masks Strongly Recommended but Not Required in Maryland, Starting Immediately

Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

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Johns Hopkins Medicine Clinical Research

Message from the Vice Dean

Gail Daumit , Vice Dean for Clinical Investigation, has released her plans for the future of the Clinical Research program. Learn about updates and expansions in her open letter.

Funding Opportunities

Junior and midlevel faculty member grant accelerator program application deadlines: june 1, 2024; october, 1 2024; and february, 1 2025.

The Grant Accelerator Program will provide onetime grants of $5,000–$15,000 to provide Core Coins for junior and midlevel faculty members and help them overcome barriers to successful grant submissions. These small awards provide a way to rapidly fund data acquisition and analysis that investigators need as part of their grant applications. The funds may be spent at any of the Cores on iLabs for clinical or laboratory projects. In addition to the funding, Core staff will be available to help applicants design analyses and interpret data.

The Grant Accelerator application is quick and easy to complete, requiring only a few brief responses and a one-page NIH format specific aims page . The application is available .

Upcoming application deadlines are June 1, Oct. 1 and Feb. 1 , and we expect to fund 20–35 projects each cycle. Decisions and funding will be provided within one month of each application deadline. 

Monday, June 10, 2024, 8th Annual Johns Hopkins Sleep & Circadian Research Day

The Johns Hopkins Sleep & Circadian Research Day brings together sleep and circadian researchers from institutions across the region. Purpose is to provide a venue for networking and communication in the field, as well as a platform for trainees to present their research.

Keynote speaker this year will be  Dr. David Rapoport,  who is Director of the Sleep Medicine Research Program at Mount Sinai. He is a pioneer in the study of the physiology and treatment of sleep apnea and founded the Foundation for Research in Sleep Disorders.

Please pre-register by May 10, 2024 to be guaranteed a lunch! Event will be held in-person at the Turner Concourse and Tilghman Auditorium

National Institute for Health Care Management Foundation’s investigator-initiated research grant program accepting letters of inquiry by June 28th 2024

NIHCM is now accepting  letters of inquiry for the 2024-2025  funding  cycle of NIHCM Foundation's investigator-initiated research grant program. Building on our long-standing commitment to supporting objective research, NIHCM will make up to $500,000 available this year.  Seeking studies with strong potential to inform policy or have a positive impact on the U.S. health care system by improving efficiency, quality, access to care, or equity. To Apply: Submit a brief letter of inquiry through our online entry system.   Deadline June 28, 2024 5pm.

What's New?

Updated facilities and administration rate for off-campus commercial sponsored research effective july 1, 2024.

Due to increased investment in administrative infrastructure to support SOM-sponsored research, the off-campus rate for new commercial sponsored research awards will increase to 39 % from the current 34%, effective July 1, 2024. 

The on-campus rate of 72% remains unchanged.

The new off-campus rate applies to all new proposals for commercial sponsored research submitted on or after July 1, 2024. Existing awards will continue under the rate in effect as of the date of their original submission, as will any pending proposals submitted before July 1, 2024.

The Office of Federal Strategy Resources

The Office of Federal Strategy has developed the following resources to help faculty navigate through preparing for Congressional testimony, submitting effective comments to federal agencies, and best practices for moderating discussions with elected or appointed officials.

Tips for preparing Congressional testimony

Tips for submitting effective comments

Guide for moderators or facilitators

Lobbying FAQ  

Data Trust Resources

Data Trust office hours: Third Thursday of the month 8:30-9:30am via the Office Hours MS Teams channel . You can also find the library of recorded sessions .

The Research Data Subcouncil has several resources to guide study teams and answer questions about the Data Trust review process, the Risk Tiers Calculator, and access to and sharing of JHM data.

The Data Trust oversees the use and disclosure of JHM patient and plan member data stored in clinical enterprise systems. Visit the Data Trust site to learn more about data governance and best practices for JHM data.

Institutional Review Board Assistance

April 1, 2024 – update to clinical research hospital billing charges.

For those involved in clinical research hospital billing, please note that hospital billing statements generated after April 1, 2024 Hospital Billing (HB) charges from Johns Hopkins Health System facilities in Maryland will be discounted to 29.6% of the facility charge master for Government/Not for Profit organizations and to 44.4% for Pharmaceutical/For Profit sponsors. This is an increase from the previous research discount. Hospital Billing charges from Sibley Memorial Hospital and All Children’s Hospital will have an additional discount applied to maintain consistency across the Johns Hopkins Health System. See letter  for more information.

For any questions, please contact the Clinical Research Support Services (CRSS) team at [email protected] .

CCDA adjunct costs for 2024

Effective fiscal year 2024, we will be implementing the following fee structure for participating in the CCDA adjunct program. See letter  for more information.

• Annual support fee: $5,000 per CCDA adjunct and $4,000 per registry data manager. CCDA adjuncts have access to pull data from various institutional data sources and thus typically require more CCDA staff support; registry data managers are limited to the data in their provisioned registry and need less support.
• One-time onboarding fee: $5,000 for new CCDA adjuncts and registry data managers. This fee covers interviewing candidates proposed by the sponsoring department, initial training, mentoring, and review. This fee is in addition to the annual support fee.

Updates to the Human Subjects Research Compliance Training Registration Process

New ways to communicate with the office of human subjects research (ohsr) and the institutional review board (irb).

The OHSR and IRB staff have two new ways to communicate with you:

• Microsoft Teams. On the Contact page, you can find contact information for staff members, including new Microsoft Teams phone numbers, email addresses and newly added links to chat with a staff member.

Request a Consult . If you want a comprehensive discussion about, e.g., protocol planning assistance, please request a consult , and the OHSR staff will connect you with an appropriate team member.

The IRB and Data Trust streamline data sharing across JHU

Data protection attestation has been integrated into eIRB and public health institutional review system tracking (PHIRST) to enable sharing of limited data sets among Johns Hopkins University (JHU) researchers. This change eliminates the need for a data use agreement for most transfers of a limited data set to JHU collaborators. New guidance is now available to help JHU researchers?navigate the process?and requirements?for requesting use of Johns Hopkins Medicine (JHM) data.

• Review information on sharing Johns Hopkins Medicine data on the JHM Data Trust intranet site.?
• For more information on data protection attestation, see frequently asked questions.

Interested in research using artificial intelligence?

Johns hopkins office of clinical trials.

The new Johns Hopkins Office of Clinical Trials (JH-OCT) will help Johns Hopkins clinical investigators and research teams to push the boundaries of discovery with unparalleled support to develop, initiate and conduct clinical trials within the framework of human research participant protection and regulatory compliance. The JH-OCT brings together three groups in the school of medicine Office of Research Administration that provide essential services to efficiently move clinical trials contracts and budgets forward:  clinical research contracting, clinical research support services and clinical research billing compliance . JH-OCT is the gateway for clinical investigators to find the tools, resources and support required to advance discovery and clinical care in our community and beyond.

Mark Sulkowski, MD Professor of Medicine Senior Associate Dean for Clinical Trials

Institutional Review Board (IRB)

Institute for clinical and translational research, office of research administration (ora, for noncommercial funders), ora clinical research contracting (for commercial sponsors), clinical research support services (for planning and budgeting of clinical trials), investigational drug service, clinical research billing compliance, research it.

PCRS Network

Saving and improving lives by accelerating clinical research.

Every year, over 46,500,000 people die worldwide from diseases.

Inefficiencies in clinical trials add significant time and cost to bring lifesaving drugs and therapies to market. By introducing efficiencies to the clinical research model, PCRS helps reduce delays and, ultimately, save and improve lives.

Sponsors & CROs

PCRS Network simplifies the process for sponsors and CROs by providing access to member sites meeting the highest standards of quality and productivity. We accelerate the clinical research phase of development to minimize the time required to complete clinical research and get qualifying drugs and devices to market.

I'm a Sponsor or CRO

PCRS Network is an exclusive network of independently owned research sites, working together to save and improve lives by accelerating clinical research. Only high performing sites are accepted to the PCRS Network. We work very closely with our Member Sites and CRO/sponsor partners to help streamline and accelerate the site selection process.

The combination of high quality, high productivity, and increased efficiency make for a winning combination for the Sponsor, CRO, and Site.

Only the best, most productive clinical research sites meet our requirements . . .

• Members are accepted into the network through a rigorous qualification process
• Historically high enrollment, retention, completion, and evaluable data rates
• Centralized budget and contract processes result in time and cost savings
• Prompt turnaround times on regulatory submissions and data entry
• Continuous review of site quality and productivity met rics

Nutraceutical Clinical Trials Unlock Missing Revenue

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Privacy Overview

Clinical Trials

Find a clinical trial.

Learn About Clinical Research

Why participate in a clinical trial? Because it can help you while also helping others.

Clinical trials make finding new and improved medicines possible. And we can’t conduct trials without help from people like you. Every clinical trial participant provides valuable information that might help advance medical research and knowledge.

People take part in clinical trials for many reasons. For some, it’s the chance to help find cures and treatments that will benefit people in the future. It can also offer study-related health monitoring.

Looking for more details on what to expect from our clinical trials? Find more information  here . 

You can also learn about our commitment to diversity in clinical trials  here .

Clinical Trials Transparency

We have a history of transparency when it comes to our clinical studies. In 2004, we became the first company to voluntarily disclose our clinical studies initiation and post-study results in a publicly available registry.

Since the start of 2014, we have enhanced our transparency initiatives to align with the  PhRMA/EFPIA Principles for Responsible Clinical Trial Data Sharing . We recognize that sharing clinical study data can enhance public health. But responsibly sharing that data is necessary to safeguard the privacy of patients, respect the integrity of national regulatory systems, and maintain incentives for investments in biomedical research.

Expand accordion Clinical Trial Registration

• Phase 2, phase 3 and phase 4 clinical trials initiated on or after October 15, 2002
• Phase 1 clinical trials in patients initiated on or after October 1, 2009
• Phase 1 clinical trials in healthy subjects initiated on or after October 1, 2010

Expand accordion Clinical Trial Results

Expand accordion observational studies registration and results.

• Prospective effectiveness studies evaluating the extent to which treatment with a Lilly marketed product improves patient outcomes compared to the alternative treatments in actual clinical practice.
• Prospective pharmacoepidemiologic studies, i.e., studies that are designed to assess the risk attributed to a drug exposure.
• Retrospective pharmacoepidemiologic studies, i.e., studies that are designed to assess the risk attributed to a drug exposure.
• Initially, observational studies that were started on or after September 1, 2007 are located at clinicaltrials.gov or Lilly’s clinical study report synopses site.
• Starting in 2014, Lilly started registering and posting results to observational/non-interventional studies on the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP®).

Expand accordion Clinical Study Data-Sharing

Expand accordion sharing results with patients, expand accordion publication policy.

Independent Clinical Research

In addition to sponsoring our own clinical research and research collaborations, we also have programs that allow us to support external requests. We can provide resources and/or financial support for independent clinical research that is initiated, designed and sponsored by external researchers. 

We consider independent clinical research projects based on scientific merit and strategic fit with our areas of research interest. These reviews are carried out by global committees composed of Lilly medical and scientific staff members from relevant therapeutic areas.

Health care and research professionals may  submit a concept online .

Lilly Trial Experience

Study Identification - WCG Site Network

Access hundreds of new clinical trial opportunities for your clinical research site. By joining the WCG Site Network, we can help you grow your site, reduce administrative burden, and increase options for your patients.

Identify new clinical trial opportunities for your research site and grow your research program.

Explore the WCG Site Network, where study identification meets seamless site support. We offer a no out-of-pocket cost, non-exclusive partnership for independent research sites and community hospitals seeking to grow their research site.

Whether you’re looking for more study leads or want to increase options for your patients and community, we’ve got you covered. In addition to study identification, our WCG Site Network services include study start-up support, recruitment and enrollment assistance, financial management, and more, ensuring your site’s success every step of the way.

Why Clinical Research Sites Join the WCG Site Network

Access to more trials and new therapeutic areas.

Every year, we identify over 300 clinical trial opportunities for the sites in our network, in virtually every therapeutic area to help them grow their research programs.

No Out-of-Pocket Costs or Exclusive Agreements

The sites in our network are not required to sign long-term contracts or exclusive agreements and do not pay any out-of-pocket expenses to receive study leads.

Reduced Administrative Burden

Our network sites have more time to focus on patient care by outsourcing business development, feasibility, budgets, contracts, and payment reconciliation to our experts.

Exposure to More Sponsors and CROs

Sites in our network benefit from our hundreds of connections to the best sponsors and CROs in our industry.

Personalized Study Management

Sites gain access to specialized account managers that help manage the site selection, budgeting, contracting, and payment reconciliation processes.  

Increased Options for Patients and Community

Our services help the sites in our network increase their capacity to conduct clinical trials and bring additional options to their patients and communities.

WCG Site Network Members Get Access to:

Study identification support, budget development and negotiation support, contract negotiation support, financial management and payment reconciliation, recruitment and enrollment support, wcg ibc registration, pi, gcp, crc, and site training, magi clinical research conference discounts, wcg avoca quality consortium, real results from the wcg site network, studies placed in our network in the last 5 years, new study opportunities secured for our network every year, identify more clinical trial opportunities for your site.

Ready to get started? Fill out this form for a complimentary consultation with our site development manager to learn how we can help your clinical research site find more studies.

Recent insights

There is Value to Patients When Independent Sites Offer Clinical Trials

WCG Releases 2023 Report on Top Issues Impacting Clinical Research Sites

Better Together: How to Strengthen Sponsor and Site Partnerships – A Panel Discussion

Cutting Through the Noise: Use Cases for Imaging Core Labs and Endpoint Adjudication

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FDA's Role: ClinicalTrials.gov Information

Federal law requires responsible parties to register with and submit results information to the ClinicalTrials.gov data bank for certain applicable clinical trials . 

Transparency of clinical trial information is important to scientific advancement. Registering certain trials and posting summary results information permits the scientific community to build on the information made available. The public’s participation in clinical trials makes it possible to further advance scientific progress. Posting clinical trial information on ClinicalTrials.gov honors volunteers who participate in research to advance medical science and enhances public trust by creating a transparent and robust public record of clinical trials and information about their results.

Federal law requires:

• A certification of compliance with ClinicalTrials.gov requirements to accompany certain human drug, biological product and device applications and submissions to FDA.
• The inclusion of a particular statement (see below) in the informed consent documents for applicable clinical trials, which are trials that will be entered into the ClinicalTrials.gov databank. 
• FDA to oversee compliance and take appropriate enforcement action related to failure to submit required clinical trial information to ClinicalTrials.gov.

Requirements for Certification of Compliance with Certain Product Applications

FDA developed Form FDA 3674 which may be used to provide certification. The certification must accompany certain human drug, biological product and device applications and submissions. In general, FDA recommends that Form FDA 3674 accompany the following applications and submissions to FDA:

• Investigational New Drug Application (IND)
• New Clinical Protocol Submitted to an IND
• New Drug Application (NDA)
• Efficacy Supplement to an Approved NDA
• Biologics License Application (BLA)
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• Humanitarian Device Exemption (HDE)
• 510(k) submissions that refer to, relate to or include information on a clinical trial

Federal law does not require the submission of a Form FDA 3674 with an Investigational Device Exemption (IDE) application.

More information is available in FDA Guidance on Form FDA 3674 .  

Informed Consent Requirements

Federal law requires the following exact statement to be included in the informed consent documents of applicable clinical trials :

“A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

See FDA’s guidance on Informed Consent Elements, 21 CFR 50.25(c) for more information. 

ClinicalTrials.gov Compliance and Enforcement Activities

The FDA’s compliance activities related to the ClinicalTrials.gov requirements provide the opportunity for responsible parties to take voluntary corrective actions before the agency proceeds with enforcement action. The agency uses a risk-based approach to compliance and enforcement to prioritize the greatest risks to public health. 

The final guidance on Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank outlines FDA’s approach to its compliance and enforcement activities related to ClinicalTrials.gov, including potential civil money penalties for violations.

See pre-notices of noncompliance and notices of noncompliance for more information. 

Questions Related to ClinicalTrials.gov

See Submit Studies to ClinicalTrials.gov PRS for information about registering clinical trials on ClinicalTrials.gov. Contact [email protected] with questions related to:

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Contact [email protected] with questions about compliance and enforcement of ClinicalTrials.gov requirements. 

Complaints to FDA should be reported to the office handling the type of study involved. See FDA contact information for complaints .

Additional resources

• ClinicalTrials.gov – a Three-Part Series
• Final Rule on Clinical Trials Registration and Results Information Submission  
• ClinicalTrials.gov - Pre-Notices for Potential Noncompliance  
• ClinicalTrials.gov - Notices of Noncompliance and Civil Money Penalty Actions
• ClinicalTrials.gov regulations (42 CFR Part 11)
• Details of the statutory language of Title VIII of FDAAA
• NIH Checklist for evaluating whether a clinical trial is an applicable clinical trial  
• Form FDA 3674 (including instructions)
• FDA Guidance on Form FDA 3674
• FDA Guidance on Informed Consent Elements at 21 CFR 50.25(c)
• FDA guidance on Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank

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Since our inception in 1997, TRIO has been at the forefront of clinical cancer research. We have built deep relationships with highly experienced, sought-after Investigators who are pivotal to our success and recognized for their contributions.

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NIH will bring clinical research into primary care offices with $30 million pilot

By Annalisa Merelli June 7, 2024

F or many Americans, health care means going to a local primary care office. But the vast majority of clinical research is conducted inside the walls of large, specialized academic health centers. Millions of patients are left out of those studies, which often fail to capture the population in all its diversity.

Now, for the first time, the National Institutes of Health is investing in the creation of a national primary care research network to try to address this issue. Its $30 million pilot program, called Communities Advancing Research Equity for Health and announced on Thursday, will fund and support a small number of primary care sites as they participate in a range of clinical trials.

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“This is an incredibly exciting opportunity,” said Diane Harper, a primary care physician and professor in family medicine at the University of Michigan, Ann Arbor. Instead of running individual, siloed research projects out of specialized sites, the program will allow network members to participate in several trials — choosing between 20 to 30 studies — to match their local population’s health needs.

“A person is not a disease, and most of the NIH is organized around diseases,” said Harper. “This is the first time that NIH is recognizing that people are complex, and have many factors that pertain to their health care … that cannot be teased out and separated to be studied in a single, particular line.”

Related: NIH-funded clinical trials often miss racial, gender diversity enrollment goals, report finds

The pilot is an opportunity to better understand how research can serve the needs of patients outside traditional settings, said NIH Director Monica Bertagnolli. “We know that every community is different, and we cannot just assume that a rural community in Alabama is going to be the same as a rural community in Montana or that their health issues are the same,” she said. “What we want to do is to be able to offer any community a whole bunch of different research opportunities,” learning through experience what they find most meaningful.

The research projects will go beyond drug trials to emphasize issues that are acutely experienced by communities facing health disparities, including substance use, mental health disorders, and obesity.

The timeline is tight: The NIH hopes to award funding very soon, and hold its first investigator meeting by the winter. The focus on a speedy start, said Harper, is not giving primary care sites sufficient time to apply for the funding deadline, which is set for next week. As a result, she worries the first round of research will be led by academic networks with links to primary care. “These are not primary care networks,” she said. “These are Ph.D.s with ideas about what it means to be in primary care, it’s not the people who practice.”

The accelerated timeline was put in place to support a launch by the end of fiscal year 2024, said NIH spokesperson Renate Myles, while still allowing the application period to be open for about six weeks. “We expect more opportunities in future years for potential applicants who were unable to participate this year,” she said.

This isn’t the first experiment with primary care research networks. “There’s many folks who’ve worked for a long time to help the NIH get to this point where they’re ready to take their research out of the academic medical center into rural and frontier and underserved community practices,” said Jack Westfall, a rural primary care physician and retired professor at the University of Colorado.

In the late 1990s, Westfall helped establish the High Plains Research Network, a research network of all the primary care practices in eastern, rural, and frontier Colorado towns — most with just a few thousand residents each. He’s found that community-based studies can pay dividends for researchers, too.

“The NIH research needs to move outside of the academic medical centers, out into the community, out into the primary care practices, both for finding study subjects, but also for finding research ideas,” said Westfall. “Many times there are clinical questions that come up out of the community, from the patients, from their interactions with their physicians that could generate ongoing ideas for research.”

Related: Inside a push to create an NIH office for post-infection chronic illness

The NIH also sees the program as an opportunity to gain trust from communities that are skeptical of the medical establishment. “We are here to understand what people need and to earn their trust by delivering for them,” said Bertagnolli. “Trust is not automatic, it has to be earned.”

To build that trust, the network will have to be careful not to treat patients and their local providers like cogs in a machine. “The risk is that this will just be extractive, not collaborative,” said Westfall. “We want to make sure that this is not just an extraction of study subjects out of primary care and NIH, but a bidirectional flow of resources, of ideas, of topics, of power.”

“Making studies available closer to where people are actually getting treated, that’s the first step,” said Andrew Trister, chief medical and scientific officer at Verily, an Alphabet company that builds tools for clinical research. But it raises a number of important questions, he said: “What’s the chain of the trust chain? Who is trusted in the community? Who could be able to help people understand more about what the clinical study is about? Why participate in research?”

Down the line, the network could help primary care sites to mobilize more effectively in case of national health emergencies. “The Covid pandemic did not use primary care at all efficiently,” said Harper. But if the pilot is successful and expands to create a nationwide network, it could eventually enable a faster, more effective public health response — and clinical trials, to boot.

About the Author Reprints

Annalisa merelli.

General Assignment Reporter

Annalisa (Nalis) Merelli is a general assignment reporter at STAT. Her interests are ever-expanding, but she is especially drawn to the coverage of reproductive and maternal health, and their intersection with health equity.

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News releases.

News Release

Thursday, June 6, 2024

NIH launches $30 million pilot to test feasibility of a national primary care research network

Initiative aims to improve health outcomes by integrating research in everyday primary care settings.

CARE for Health infographic

The National Institutes of Health (NIH) is investing approximately $30 million in total over fiscal years 2024 and 2025 to pilot a national primary care research network that integrates clinical research with community-based primary care. The new initiative called Communities Advancing Research Equity for Health – or CARE for Health – seeks to improve access to clinical research to inform medical care, particularly for those in communities historically underrepresented in clinical research or underserved in health care. Informed by the health needs of these communities, CARE for Health will help to grow an evidence base that contributes to improved patient outcomes, provide communities access to the best available scientific research and expand opportunities to participate in clinical trials and studies. NIH Director Monica M. Bertagnolli, M.D., lays out her vision for CARE for Health in a Science Editorial that was published today.

“Despite tremendous scientific progress, the health of important segments of the U.S. population is getting worse, not better,” said Dr. Bertagnolli. “Health is dependent upon many factors.  We recognize that environmental and societal factors are very important, and that each community is unique. Because of this, we must adapt our research to be more inclusive and more responsive to the needs of communities currently underserved in health research. Our vision for CARE for Health is to help primary care providers and their patients contribute to knowledge generation, and to deliver evidence back to them to achieve better care.”

Supported through the NIH Common Fund, CARE for Health will initially leverage existing NIH-funded clinical research networks and community partners to establish the infrastructure that will support research at select primary care sites. Initial awards will fund organizations that serve rural communities and are expected to be made in fall 2024.

“Health research should be accessible to all populations. Clinical trials should reflect the diversity of Americans – because we know that delivers the best results,” said HHS Secretary Xavier Becerra. “We are taking a big step towards ensuring communities that are historically underrepresented in clinical research are fully included and have the same access to the best available results and analysis. There has never been more potential for progress than we have today.”

Participating clinical sites will be able to choose research studies based on health issues affecting and prioritized by their communities. Patients will be able to contribute their data to research in order to generate results that are clinically meaningful to them. Final study findings and aggregate results will be shared with research participants. CARE for Health will expand NIH-funded research studies to increase engagement with people from communities historically underrepresented or underserved in health care and clinical research. This includes people from certain racial and ethnic groups, those who are older, those who live in rural areas and those who have low socioeconomic status or lower educational attainment. Studies will seek to address common health issues, as well as disease prevention.  

“Community-oriented primary care not only provides essential health services, but it also engenders trust among those who lack confidence in recommended medical care or science,” said Dr. Bertagnolli. “In fact, greater availability of primary care services in communities is associated with fewer disparities in health outcomes and lower mortality. We earn people’s trust when they get access to the care they need and when they can see direct benefits from their participation in research.”

As CARE for Health expands, the program will launch new studies across the network and further establish study sites, training capabilities, data management and increased interoperability. By expanding collaborations to integrate research data into clinical practice and clinical data collection into research studies, the network will facilitate the use of innovative practices and trial designs to minimize burden of research on primary care providers and patients.

“The goal is to create a learning health system in which research informs clinical practice and clinical data informs research,” said NIH Deputy Director for Program Coordination, Planning, and Strategic Initiatives Tara A. Schwetz, Ph.D. “As the program grows, sites and their communities will help design new clinical studies reflecting their specific health needs, and results from those studies will inform the care they receive.”

The NIH is hosting a public workshop on Friday, June 7 from 10 a.m. to 12:30 p.m. EDT to share findings from a series of listening sessions on the challenges and opportunities for integrating research into primary care. Learn more about the workshop and register for the event .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Clinical Practice Guidelines and Dental Evidence

Clinical practice guidelines.

The strongest resources to aid dental professionals in clinical decision-making. Developed by an expert panel, clinical practice guidelines critically appraise, summarize, and interpret recent and relevant clinical evidence to provide recommendations that can be applied to patient care. Explore current clinical practice guidelines below.

Recommendations for managing acute dental pain in children, adolescents and adults after tooth extraction(s) or for the temporary management of toothache.

Recommendations for the use of 16 restorative caries treatments – which direct restorative materials and caries removal approaches to use.

Clinical recommendations for the use of nine nonrestorative caries treatments, including the ADA's first-ever recommendations for silver diamine fluoride (SDF).

The latest recommendations for antibiotic usage in the urgent management of pulpal- and periapical-related dental pain and intra-oral swelling.

Recommendations from the American Heart Association on the use of antibiotics to prevent infective endocarditis.

Recommendations for the use of antibiotic prophylaxis to prevent orthopaedic implant infection in dental patients.

Updated guideline recommending a unified message to the general public regarding fluoride toothpaste usage for children under six years of age.

Clinical recommendations for the use of agents such as sucrose-free polyol chewing gums, xylitol dentifrices, and chlorhexidine in preventing caries.

Current recommendations for evaluating lesions, including potentially malignant disorders, in the oral cavity of patients.

ADA panel recommendations for nonsurgical treatment of chronic periodontitis by means of scaling and root planing with or without adjuncts.

Expert panel recommendations for the use of pit-and-fissure sealants to prevent caries.

ADA panel recommendations for various topical fluoride agents for caries prevention, including mouth rinses, varnishes, gels, foams and pastes.

Systematic reviews

Like clinical practice guidelines, systematic reviews critically appraise and summarize the scientific literature in regards to a specific clinical question. Unlike guidelines, which then use the literature to make clinical recommendations, systematic reviews leave the job of interpreting their results up to the discretion of dental practitioners. Explore our collection of current systematic reviews below.

Preradiotherapy dental treatment’s effect on the risk of osteoradionecrosis of the jaw during oncologic treatment.

Use of communication systems and information-based technologies to promote oral health.

Technologies to detect and inform the diagnosis of initial caries.

Analyzing HPV vaccine effectiveness against vaccine-type HPV infection and HPV-associated cellular changes.

Primary studies

The ADA provides relevant research data that you can use for clinical decision making. Explore the most recent and trending topics below.

How to overcome common challenges to guideline adoption in dental practice.

Assessing the prevalence of anxiety and depression symptoms among dental health care workers during the COVID-19 pandemic.

As of August 2021, 75.4% of hygienists had been fully vaccinated against COVID-19, a higher proportion than the general public and health care workers overall.

Want to learn how to incorporate the latest scientific evidence into clinical practice? Check out these educational opportunities offered by the ADA Science and Research Institute.

Explore various instructional videos that help illustrate certain evidence-based dentistry techniques and clinical procedures.

Learn how both dental teams and educators can harness the power of the latest scientific information and apply it to patient care.

Evidence-Based Dentistry

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Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial

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• Anne Ornish 1 ,
• Sarah Tranter 8 ,
• Nancy DeLamarter 1 ,
• Noel Wingers 1 ,
• Carra Richling 1 ,
• Rima Kaddurah-Daouk 18 ,
• Rob Knight 19 ,
• Daniel McDonald 20 ,
• Lucas Patel 21 ,
• Eric Verdin 22 , 23 ,
• Rudolph E. Tanzi 13 , 24 , 25 , 26 &
• Steven E. Arnold 13 , 27  

Alzheimer's Research & Therapy volume  16 , Article number:  122 ( 2024 ) Cite this article

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Evidence links lifestyle factors with Alzheimer’s disease (AD). We report the first randomized, controlled clinical trial to determine if intensive lifestyle changes may beneficially affect the progression of mild cognitive impairment (MCI) or early dementia due to AD.

A 1:1 multicenter randomized controlled phase 2 trial, ages 45-90 with MCI or early dementia due to AD and a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The primary outcome measures were changes in cognition and function tests: Clinical Global Impression of Change (CGIC), Alzheimer’s Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks of an intensive multidomain lifestyle intervention compared to a wait-list usual care control group. ADAS-Cog, CDR-SB, and CDR-Global scales were compared using a Mann-Whitney-Wilcoxon rank-sum test, and CGIC was compared using Fisher’s exact test. Secondary outcomes included plasma Aβ42/40 ratio, other biomarkers, and correlating lifestyle with the degree of change in these measures.

Fifty-one AD patients enrolled, mean age 73.5. No significant differences in any measures at baseline. Only two patients withdrew. All patients had plasma Aβ42/40 ratios <0.0672 at baseline, strongly supporting AD diagnosis. After 20 weeks, significant between-group differences in the CGIC ( p = 0.001), CDR-SB ( p = 0.032), and CDR Global ( p = 0.037) tests and borderline significance in the ADAS-Cog test ( p = 0.053). CGIC, CDR Global, and ADAS-Cog showed improvement in cognition and function and CDR-SB showed significantly less progression, compared to the control group which worsened in all four measures. Aβ42/40 ratio increased in the intervention group and decreased in the control group ( p = 0.003). There was a significant correlation between lifestyle and both cognitive function and the plasma Aβ42/40 ratio. The microbiome improved only in the intervention group ( p <0.0001).

Conclusions

Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in many patients with MCI or early dementia due to AD.

Trial registration

Approved by Western Institutional Review Board on 12/31/2017 (#20172897) and by Institutional Review Boards of all sites. This study was registered retrospectively with clinicaltrials.gov on October 8, 2020 (NCT04606420, ID: 20172897).

Increasing evidence links lifestyle factors with the onset and progression of dementia, including AD. These include unhealthful diets, being sedentary, emotional stress, and social isolation.

For example, a Lancet commission on dementia prevention, intervention, and care listed 12 potentially modifiable risk factors that together account for an estimated 40% of the global burden of dementia [ 1 ]. Many of these factors (e.g., hypertension, smoking, depression, type 2 diabetes, obesity, physical inactivity, and social isolation) are also risk factors for coronary heart disease and other chronic illnesses because they share many of the same underlying biological mechanisms. These include chronic inflammation, oxidative stress, insulin resistance, telomere shortening, sympathetic nervous system hyperactivity, and others [ 2 ]. A recent study reported that the association of lifestyle with cognition is mostly independent of brain pathology, though a part, estimated to be only 12%, was through β-amyloid [ 3 ].

In one large prospective study of adults 65 or older in Chicago, the risk of developing AD was 38% lower in those eating high vs low amounts of vegetables and 60% lower in those consuming omega-3 fatty acids at least once/week, [ 4 ] whereas consuming saturated fat and trans fats more than doubled the risk of developing AD [ 5 ].A systematic review and meta-analysis of 243 observational prospective studies and 153 randomized controlled trials found a similar relationship between these and similar risk factors and the onset of AD [ 6 ].

The multifactorial etiology and heterogeneity of AD suggest that multidomain lifestyle interventions may be more effective than single-domain ones for reducing the risk of dementia, and that more intensive multimodal lifestyle interventions may be more efficacious than moderate ones at preventing dementia [ 7 ].

For example, in the Finnish Geriatric Intervention Study (FINGER) study, a RCT of men and women 60-77 in age with Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk scores of at least 6 points and cognition at mean or slightly lower, a multimodal intervention of diet, exercise, cognitive training, vascular risk monitoring maintained cognitive function after 2 years in older adults at increased risk of dementia [ 8 ]. After 24 months, global cognition in the FINGER intervention group was 25% higher than in the control group which declined. Moreover, the FINGER intervention was equally beneficial regardless of several demographic and socioeconomic risk factors [ 9 ] and apolipoprotein E (APOE) ε4 status [ 10 ].

The FINGER lifestyle intervention also resulted in a 13-20% reduction in rates of cardiovascular disease events (stroke, transient ischemic attack, or coronary), providing more evidence that “what’s good for the heart is good for the brain”(and vice versa) [ 11 ]. Other large-scale multidomain intervention studies to determine if this intervention can help prevent dementia are being conducted or planned in over 60 countries worldwide, as part of the World-Wide FINGERS network, including the POINTER study in the U.S. [ 12 , 13 ].

More recently, a similar dementia prevention-oriented RCT showed that a 2-year personalized multidomain intervention led to modest improvements in cognition and dementia risk factors in those at risk for (but not diagnosed with) dementia and AD [ 14 ].

All these studies showed that lifestyle changes may help prevent dementia. The study we are reporting here is the first randomized, controlled clinical trial to test whether intensive lifestyle changes may beneficially affect those already diagnosed with mild cognitive impairment (MCI) or early dementia due to AD.

In two earlier RCTs, we found that the same multimodal lifestyle intervention described in this article resulted in regression of coronary atherosclerosis as measured by quantitative coronary arteriography [ 15 ] and ventricular function, [ 16 ] improvements in myocardial perfusion as measured by cardiac PET scans, and 2.5 times fewer cardiac events after five years, all of which were statistically significant [ 17 ]. Until then, it was believed that coronary heart disease progression could only be slowed, not stopped or reversed, similar to how MCI or early dementia due to AD are viewed today.

Since AD and coronary heart disease share many of the same risk factors and biological mechanisms, and since moderate multimodal lifestyle changes may help prevent AD, [ 18 ] we hypothesized that a more intensive multimodal intervention proven to often reverse the progression of coronary heart disease and some other chronic diseases may also beneficially affect the progression of MCI or early dementia due to AD.

We report here results of a randomized controlled trial to determine if the progression of MCI or early dementia due to AD may be slowed, stopped, or perhaps even reversed by a comprehensive, multimodal, intensive lifestyle intervention after 20 weeks when compared to a usual-care randomized control group. This lifestyle intervention includes (1) a whole foods, minimally processed plant-based diet low in harmful fats and low in refined carbohydrates and sweeteners with selected supplements; (2) moderate exercise; (3) stress management techniques; and (4) support groups.

This intensive multimodal lifestyle modification RCT sought to address the following questions:

Can the specified multimodal intensive lifestyle changes beneficially affect the progression of MCI or early dementia due to AD as measured by the AD Assessment Scale–Cognitive Subscale (ADAS-Cog), CGIC (Clinical Global Impression of Change), CDR-SB (Clinical Dementia Rating Sum of Boxes), and CDR-G (Clinical Dementia Rating Global) testing?

Is there a significant correlation between the degree of lifestyle change and the degree of change in these measures of cognition and function?

Is there a significant correlation between the degree of lifestyle change and the degree of change in selected biomarkers (e.g., the plasma Aβ42/40 ratio)?

Participants and methods

This study was a 1:1 multi-center RCT during the first 20 weeks of the study, and these findings are reported here. Patients who met the clinical trial inclusion criteria were enrolled between September 2018 and June 2022.

Participants were enrolled who met the following inclusion criteria:

Male or female, ages 45 to 90

Current diagnosis of MCI or early dementia due to AD process, with a MoCA score of 18 or higher (National Institute on Aging–Alzheimer’s Association McKhann and Albert 2011 criteria) [ 19 , 20 ]

Physician shared this diagnosis with the patient and approved their participation in this clinical trial

Willingness and ability to participate in all aspects of the intervention

Availability of spouse or caregiver to provide collateral information and assist with study adherence

Patients were excluded if they had any of the following:

Moderate or severe dementia

Physical disability that precludes regular exercise

Evidence for other primary causes of neurodegeneration or dementia, e.g., significant cerebrovascular disease (whose primary cause of dementia was vascular in origin), Lewy Body disease, Parkinson's disease, FTD

Significant ongoing psychiatric or substance abuse problems

Fifty-one participants with MCI or early-stage dementia due to AD who met these inclusion criteria were enrolled between September 2018 and June 2022 and underwent baseline testing. 26 of the enrolled participants were randomly assigned to an intervention group that received the multimodal lifestyle intervention for 20 weeks and 25 participants were randomly assigned to a usual habits and care control group that was asked not to make any lifestyle changes for 20 weeks, after which they would be offered the intervention. Patients in both groups received standard of care treatment managed by their own neurologist.

The intervention group received the lifestyle program for 20 weeks (initially in person, then via synchronous Zoom after March 2020 due to COVID-19). Two participants who did not want to continue these lifestyle changes withdrew during this time, both in the intervention group (one male, one female). Participants in both groups completed a follow-up visit at 20 weeks, where clinical and cognitive assessments were completed. Data were analyzed comparing the baseline and 20 week assessments between the groups.

In a drug trial, access to an investigational new drug can be restricted from participants in a randomized control group. However, we learned in our prior clinical trials of this lifestyle intervention with other diseases that it is often difficult to persuade participants who are randomly assigned to a usual-care control group to refrain from making these lifestyle changes for more than 20 weeks, which is why this time duration was chosen. If participants in both groups made similar lifestyle changes, then it would not be possible to show differences between the groups. Therefore, to encourage participants randomly assigned to the control group not to make lifestyle changes during the first 20 weeks, we offered to provide them the same lifestyle program at no cost to them for 20 weeks after being in the usual-care control group and tested after 20 weeks.

We initially planned to enroll 100 patients into this study based on power calculations of possible differences between groups in cognition and function after 20 weeks. However, due to challenges in recruiting patients, especially with the COVID-19 emergency and that many pharma trials began recruiting patients with similar criteria, it took longer to enroll patients than initially planned [ 21 ]. Because of this, we terminated recruitment after 51 patients were enrolled. This decision was based only on recruitment issues and limited funding, without reviewing the data at that time.

Patients were recruited from advertisements, presentations at neurology meetings, referrals from diverse groups of neurologists and other physicians, and a search of an online database of patients at UCSF. We put a special emphasis on recruiting diverse patients, although we were less successful in doing so than we hoped (Table 1 ).

This clinical trial was approved by the Western Institutional Review Board on 12/31/2017 (approval number: 20172897) and all participants and their study partners provided written informed consent. The trial protocol was also approved by the appropriate Institutional Review Board of all participating sites, and all subjects provided informed consent. Due to the COVID-19 emergency, planned MRI and amyloid PET scans were no longer feasible, and the number of cognition and function tests was decreased. An initial inclusion criterion of “current diagnosis of mild to moderate dementia due to AD (McKhann et al., 2011)” was further clarified to include a MoCA score of 18 or higher. This study was registered with clinicaltrials.gov on October 8, 2020 (NCT04606420, Unique Protocol ID: 20172897) retrospectively due to an administrative error. None of the sponsors who provided funding for this study participated in its design, conduct, management, or reporting of the results. Those providing the lifestyle intervention were separate from those performing testing and from those collecting and analyzing the data, who were blinded to group assignment. All authors contributed to manuscript draft revisions, provided critical comment, and approved submission for publication.

Any modifications in the protocol were approved in advance and in writing by the senior biostatistician (Charles McCulloch PhD) or the senior expert neuropsychologist (Dorene Rentz PsyD), and subsequently approved by the WIRB.

Patients were initially recruited only from the San Francisco Bay area beginning October 2018 and met in person until February 2020 when the COVID-19 pandemic began. Subsequently, this multimodal lifestyle intervention was offered to patients at home in real time via Zoom.

Offering this intervention virtually provided an opportunity to recruit patients from multiple sites, including the Massachusetts General Hospital/Harvard Medical School, Boston, MA; the University of California, San Diego; and Renown Regional Medical Center, Reno, NV, as well as with neurologists in the San Francisco Bay Area. These participants were recruited and tested locally at each site and the intervention was provided via Zoom and foods were sent directly to their home.

Patient recruitment

This is described in the Supplemental Materials section.

Intensive multimodal lifestyle intervention

Each patient received a copy of a book which describes this lifestyle medicine intervention for other chronic diseases. [ 2 ]

A whole foods minimally-processed plant-based (vegan) diet, high in complex carbohydrates (predominantly fruits, vegetables, whole grains, legumes, soy products, seeds and nuts) and especially low in harmful fats, sweeteners and refined carbohydrates. It was approximately 14-18% of calories as total fat, 16-18% protein, and 63-68% mostly complex carbohydrates. Calories were unrestricted. Those with higher caloric needs were given extra portions.

To assure the high adherence and standardization required to adequately test the hypothesis, 21 meals/week and snacks plus the daily supplements listed below were provided throughout the 40 weeks of this intervention to each study participant and his or her spouse or study partner at no cost to them. Twice/week, we overnight shipped to each patient as well as to their spouse or study partner three meals plus two snacks per day that met the nutritional guidelines as well as the prescribed nutritional supplements.

We asked participants to consume only the food and nutritional supplements we sent to them and no other foods. We reasoned that if adherence to the diet and lifestyle intervention was high, whatever outcomes we measured would be of interest. That is, if patients in the intervention group were adherent but showed no significant benefits, that would be a disappointing but an important finding. If they showed improvement, that would also be an important finding. But if they did not follow the lifestyle intervention sufficiently, then we would not have been able to adequately test the hypotheses.

Aerobic (e.g., walking) at least 30 minutes/day and mild strength training exercises at least three times per week from an exercise physiologist in person or with virtual sessions. Patients were given a personalized exercise prescription based on age and fitness level. All sessions were overseen by a registered nurse.

• Stress management

Meditation, gentle yoga-based poses, stretching, progressive relaxation, breathing exercises, and imagery for a total of one hour per day, supervised by a certified stress management specialist. The purpose of each technique was to increase the patient’s sense of relaxation, concentration, and awareness. They were also given access to online meditations. Patients had the option of using flashing-light glasses at a theta frequency of 7.83 Hz plus soothing music as an aid to meditation and insomnia [ 22 ]. They were also encouraged to get adequate sleep.

Group support

Participants and their spouses/study partners participated in a support group one hour/session, three days/week, supervised by a licensed mental health professional in a supportive, safe environment to increase emotional support and community as well as communication skills and strategies for maintaining adherence to the program. They also received a book with memory exercises used periodically during group sessions [ 23 ].

To reinforce this lifestyle intervention, each patient and their spouse or study partner met three times/week, four hours/session via Zoom: 2

one hour of supervised exercise (aerobic + strength training)

one hour of stress management practices (stretching, breathing, meditation, imagery)

one hour of a support group

one hour lecture on lifestyle

Additional optional exercise and stress management classes were provided.

Supplements

Omega-3 fatty acids with Curcumin (1680 mg omega-3 & 800 mg Curcumin, Nordic Naturals ProOmega CRP, 4 capsules/day). Omega-3 fatty acids: In those age 65 or older, those consuming omega-3 fatty acids once/week or more had a 60% lower risk of developing AD, and total intake of n-3 polyunsaturated fatty acids was associated with reduced risk of Alzheimer disease [ 24 ]. Curcumin targets inflammatory and antioxidant pathways as well as (directly) amyloid aggregation, [ 25 ] although there may be problems with bioavailability and crossing the blood-brain barrier [ 26 ].

Multivitamin and Minerals (Solgar VM-75 without iron, 1 tablet/day). Combinatorial formulations demonstrate improvement in cognitive performance and the behavioral difficulties that accompany AD [ 27 ].

Coenzyme Q10 (200 mg, Nordic Naturals, 2 soft gels/day). CoQ10. May reduce mitochondrial impairment in AD [ 28 ].

Vitamin C (1 gram, Solgar, 1 tablet/day): Maintaining healthy vitamin C levels may have a protective function against age-related cognitive decline and AD [ 29 ].

Vitamin B12 (500 mcg, Solgar, 1 tablet/day): B12 hypovitaminosis is linked to the development of AD pathology [ 30 ].

Magnesium L-Threonate (Mg) (144 mg, Magtein, 2 tablets/day). A meta-analysis found that Mg deficiency may be a risk factor of AD and Mg supplementation may be an adjunctive treatment for AD [ 31 ].

Hericium erinaceus (Lion’s Mane, Stamets Host Defense, 2 grams/day): Lion’s mane may produce significant improvements in cognition and function in healthy people over 50 [ 32 ] and in MCI patients compared to placebo [ 33 ].

Super Bifido Plus Probiotic (Flora, 1 tablet/day). A meta-analysis suggests that probiotics may benefit AD patients [ 34 ].

Primary outcome measures: cognition and function testing

Four tests were used to assess changes in cognition and function in these patients. These are standard measures of cognition and function included in many FDA drug trials: ADAS-Cog; Clinical Global Impression of Change (CGIC); Clinical Dementia Rating Sum of Boxes (CDR-SB); Clinical Dementia Rating Global (CDR Global). All cognition and function raters were trained psychometrists with experience in administering these tests in clinical trials. Efforts were made to have the same person perform cognitive testing at each visit to reduce inter-observer variability. Those doing ADAS-Cog assessments were certified raters and tested patients in person. The CGIC and CDR tests were administered for all patients via Zoom by different raters than the ADAS-cog. Also, raters were blind to treatment arm to the degree possible.

Secondary outcome measures: biomarkers and microbiome

These are described in the Supplemental Materials section. These include blood-based biomarkers (such as the plasma Aβ42/40 ratio) and microbiome taxa (organisms).

Statistical methods

These are described in the Supplemental Materials section.

The recruitment effort for this trial lasted from 01/23/2018 to 6/16/2022. The most effective recruitment method was referral from the subjects’ physician or healthcare provider. Additional recruitment efforts included advertising in print and digital media; speaking to community groups; mentioning the study during podcast and radio interviews; collaborating with research institutions that provide dementia diagnosis and treatment; and contracting a clinical trials recruitment service (Linea). A total of 1585 people contacted us; of these, 1300 did not meet the inclusion criteria, 102 declined participation, and 132 were screening incomplete when enrollment closed, resulting in the enrollment of 51 participants (Fig. 1 ).

CONSORT flowchart: patients, demographics, and enrollment

The remaining 51 patients were randomized to an intervention group (26 patients) that received the lifestyle intervention for 20 weeks or to a usual-care control group (25 patients) that was asked not to make any lifestyle changes. Two patients in the intervention group withdrew during the intervention because they did not want to continue the diet and lifestyle changes. No patients in the control group withdrew prior to 20-week testing. Analyses were performed on the remaining 49 patients. No patients were lost to follow-up.

All of these 49 patients had plasma Aβ42/40 ratios <0.089 (all were <0.0672), strongly supporting the diagnosis of Alzheimer’s disease [ 35 ].

At baseline, there were no statistically significant differences between the intervention group and the randomized control group in any measures, including demographic characteristics, cognitive function measures, or biomarkers (Table 1  and Table 2 ).

Cognition and function testing: primary analysis

Results after 20 weeks of a multimodal intensive lifestyle intervention in all patients showed overall statistically significant differences between the intervention group and the randomized control group in cognition and function in the CGIC ( p = 0.001), CDR-SB ( p = 0.032), and CDR Global ( p = 0.037) tests and of borderline significance in the ADAS-Cog test ( p = 0.053, Table 3 ). Three of these measures (CGIC, CDR Global, ADAS-Cog) showed improvement in cognition and function in the intervention group and worsening in the control group, and one test (CDR-SB) showed significantly less progression when compared to the randomized control group, which worsened in all four of these measures.

PRIMARY ANALYSIS (with outlier included), Table 3 :

CGIC (Clinical Global Impression of Change)

These scores improved in the intervention group and worsened in the control group.

(Fisher’s exact p -value = 0.001). 10 people in the intervention group showed improvement compared to none in the control group. 7 people in the intervention group and 8 people in the control group were unchanged. 7 people in the intervention group showed minimal worsening compared to 14 in the control group. None in the intervention group showed moderate worsening compared to 3 in the control group.

CDR-Global (Clinical Dementia Rating-Global)

These scores improved in the intervention group (from 0.69 to 0.65) and worsened in the randomized control group (from 0.66 to 0.74), mean difference = 0.12, p = 0.037 (Table 3 and Fig. 2 ).

Changes in CDR-Global (lower = improved)

ADAS-Cog (Alzheimer’s Disease Assessment Scale)

These scores improved in the intervention group (from 21.551 to 20.536) and worsened in the randomized control group (from 21.252 to 22.160), mean group difference of change = 1.923 points, p = 0.053 (Table 3 and Fig. 3 ). (ADAS-Cog testing in one intervention group patient was not administered properly so it was excluded.)

Changes in ADAS-Cog (lower = improved)

CDR-SB (Clinical Dementia Rating Sum of Boxes)

These scores worsened significantly more in the control group (from 3.34 to 3.86) than in the intervention group (from 3.27 to 3.35), mean group difference = 0.44, p = 0.032 (Table 3 and Fig. 4 ).

Changes in CDR-SB (lower = improved)

There were no significant differences in depression scores as measured by PHQ-9 between the intervention and control groups.

Secondary sensitivity analyses

One patient in the intervention group was a clear statistical outlier in his cognitive function testing based on standard mathematical definitions (none was an outlier in the control group) [ 36 ]. Therefore, this patient’s data were excluded in a secondary sensitivity analysis. These results showed statistically significant differences in all four of these measures of cognition and function (Table 4 ). Three measures (ADAS-Cog, CGIC, and CDR Global) showed significant improvement in cognition and function and one (CDR-SB) showed significantly less worsening when compared to the randomized control group, which worsened in all four of these measures.

Sensitivity analysis (with outlier excluded)

There were no significant differences in depression scores as measured by PHQ-9 between the intervention and control groups in either analysis.

A reason why this patient might have been a statistical outlier is that he reported intense situational stress before his testing. As a second sensitivity analysis, this same outlier patient was retested when he was calmer, and all four measures (ADAS-Cog, CGIC, CDR Global, and CDR-SB) showed significant improvement in cognition and function, whereas the randomized control group worsened in all four of these measures.

Biomarker results

We selected biomarkers that have a known role in the pathophysiology of AD (Table 5 ). Of note is that the plasma Aβ42/40 ratio increased in the intervention group but decreased in the randomized control group ( p = 0.003, two-tailed).

Correlation of lifestyle index and cognitive function

In the current clinical trial, despite the inherent limitations of self-reported data, we found statistically significant correlations between the degree of lifestyle change (from baseline to 20 weeks) and the degree of change in three of four measures of cognition and function as well as correlations between the adherence to desired lifestyle changes at just the 20-week timepoint and the degree of change in two of the four measures of cognition and function and borderline significance in the fourth measure.

Correlation with lifestyle at 20 weeks: p = 0.052; correlation: 0.241

Correlation with degree of change in lifestyle: p = 0.015; correlation: 0.317

Correlation with lifestyle at 20 weeks: p = 0.043; correlation: 0.251

Correlation with degree of change in lifestyle: p = 0.081; correlation: 0.205

Correlation with lifestyle at 20 weeks: p = 0.065; correlation: 0.221

Correlation with degree of change in lifestyle: p = 0.024; correlation: 0.286

Correlation with lifestyle at 20 weeks: p = 0.002

Correlation with degree of change in lifestyle: p = 0.0005

(CGIC tests are non-parametric analyses, so standard effect size calculations are not included for this measure.)

Also, we also found a significant correlation between dietary total fat intake and changes in the CGIC measure ( p = 0.001), but this was not significant for the other three measures.

Correlation of lifestyle index and biomarker data

In the current clinical trial, despite the inherent limitations of self-reported data, we found statistically significant correlations between the degree of lifestyle change (from baseline to 20 weeks) and the degree of change in many of the key biomarkers, as well as correlations between the degree of lifestyle change at 20 weeks and the degree of change in these biomarkers:

Plasma Aβ42/40 ratio

Correlation with lifestyle at 20 weeks: p = 0.035; correlation: 0.306

Correlation with degree of change in lifestyle: p = 0.068; correlation: 0.266

Correlation with lifestyle at 20 weeks: p = 0.011; correlation: 0.363

Correlation with degree of change in lifestyle: p = 0.007; correlation: 0.383

LDL-cholesterol

Correlation with lifestyle at 20 weeks: p < 0.0001; correlation: 0.678

Correlation with degree of change in lifestyle: p < 0.0001; correlation: 0.628

Beta-Hydroxybutyrate (ketones)

Correlation with lifestyle at 20 weeks: p = 0.013; correlation: 0.372

Correlation with degree of change in lifestyle: p = 0.034; correlation: 0.320

Correlation with lifestyle at 20 weeks: p = 0.228; correlation: 0.177

Correlation with degree of change in lifestyle: p = 0.135; correlation: 0.219

GFAP/glial fibrillary acidic protein

Correlation with lifestyle at 20 weeks: p = 0.096; correlation: 0.243

Correlation with degree of change in lifestyle: p =0.351; correlation: 0.138

What degree of lifestyle change is correlated with improvement in cognitive function tests?

What degree of lifestyle is needed to stop or improve the worsening of MCI or early dementia due to AD? In other words, what % of adherence to the lifestyle intervention was correlated with no change in MCI or dementia across both groups? Higher adherence than this degree of lifestyle change was associated with improvement in MCI or dementia.

Correlation with lifestyle at 20 weeks: 71.4% adherence

Correlation with lifestyle at 20 weeks: 120.6% adherence

CDR-Global:

Correlation with lifestyle at 20 weeks: 95.6%

Microbiome results

There was a significant and beneficial change in the microbiome configuration in the intervention group but not in the control group.

Several taxa (groups of microorganisms) that increased only in the intervention group were consistent with those involved in reduced AD risk in other studies. For example, Blautia, which increased during the intervention in the intervention group, has previously been associated with a lower risk of AD, potentially due to its involvement in increasing γ-aminobutyric acid (GABA) production [ 37 ].  Eubacterium also increased during the intervention in the intervention group, and prior studies have identified Eubacterium genera (namely Eubacterium fissicatena) as a protective factor in AD [ 38 ].

Also, there was a decrease in relative abundance of taxa involved in increased AD risk in the intervention group, e.g., Prevotella and Turicibacter , the latter of which has been associated with relevant biological processes such as 5-HT production. Prevotella and Turicibacter have previously been shown to increase with disease progression, [ 39 ] and these taxa decreased over the course of the intervention.

These results support the hypothesis that the lifestyle intervention may beneficially modify specific microbial groups in the microbiome: increasing those that lower the risk of AD and decreasing those that increase the risk of AD. (Please see Supplement for more detailed information.)

We report the first randomized, controlled trial showing that an intensive multimodal lifestyle intervention may significantly improve cognition and function and may allay biological features in many patients with MCI or early dementia due to AD after 20 weeks.

After 20 weeks of a multimodal intensive lifestyle intervention, results of the primary analysis when all patients were included showed overall statistically significant differences between the intervention group and the randomized control group in cognition and function as measured by the CGIC ( p = 0.001), CDR-SB ( p = 0.032), and CDR Global ( p = 0.037) tests and of borderline significance in the ADAS-Cog test ( p = 0.053).

Three of these measures (CGIC, CDR Global, ADAS-Cog) showed improvement in cognition and function in the intervention group and worsening in the randomized control group, and one test (CDR-SB) showed less progression in the intervention group when compared to the control group which worsened in all four of these measures.

These differences were even clearer in a secondary sensitivity analysis when a mathematical outlier was excluded. These results showed statistically significant differences between groups in all four of these measures of cognition and function. Three of these measures showed improvement in cognition and function and one (CDR-SB) showed less deterioration when compared to the randomized control group, which worsened in all four of these measures.

The validity of these changes in cognition and function and possible biological mechanisms of improvement is supported by the observed changes in several clinically relevant biomarkers that showed statistically significant differences in a beneficial direction after 20 weeks when compared to the randomized control group.

One of the most clinically relevant biomarkers is the plasma Aβ42/40 ratio, which increased by 6.4% in the intervention group and decreased by 8.3% in the randomized control group after 20 weeks, and these differences were statistically significant ( p = 0.003, two-tailed).

In the lecanemab trial, plasma levels of the Aβ42/40 biomarker increased in the intervention group over 18 months with the presumption that this reflected amyloid moving from the brain to the plasma [ 40 ]. We found similar results in the direction of change in the plasma Aβ42/40 ratio from this lifestyle intervention but in only 20 weeks. Conversely, this biomarker decreased in the control group (as in the lecanemab trial), which may indicate increased cerebral uptake of amyloid.

Other clinically relevant biomarkers also showed statistically significant differences (two-tailed) in a beneficial direction after 20 weeks when compared to the randomized control group. These include hemoglobin A1c, insulin, glycoprotein acetyls (GlycA), LDL-cholesterol, and β-Hydroxybutyrate (ketone bodies).

Improvement in these biomarkers provides more biological plausibility for the observed improvements in cognition and function as well as more insight into the possible mechanisms of improvement. This information may also help in predicting which patients are more likely to show improvements in cognition and function by making these intensive lifestyle changes.

Other relevant biomarkers were in a beneficial direction of change in the intervention group compared with the randomized control group after 20 weeks. These include pTau181, GFAP, CRP, SAA, and C-peptide. Telomere length increased in the intervention group and was essentially unchanged in the control group. These differences were not statistically significant even when there was an order of magnitude difference between groups (as with GFAP and pTau181) or an almost four-fold difference (as with CRP), but these changes were in a beneficial direction. At least in part, these findings may be due to a relatively small sample size and/or a short duration of only 20 weeks.

We found a statistically significant dose-response correlation between the degree of lifestyle changes in both groups (“lifestyle index”) and the degree of change in many of these biomarkers. This correlation was found in both the degree of change in lifestyle from baseline to 20 weeks as well as the lifestyle measured at 20 weeks. These correlations also add to the biological plausibility of these findings.

We also found a statistically significant dose-response correlation between the degree of lifestyle changes in both groups (“lifestyle index”) and changes in most measures of cognition and function testing. In short, the more these AD patients changed their lifestyle in the prescribed ways, the greater was the beneficial impact on their cognition and function. These correlations also add to the biological plausibility of these findings. This variation in adherence helps to explain in part why some patients in the intervention group improved and others did not, but there are likely other mechanisms that we do not fully understand that may play a role. These statistically significant correlations are especially meaningful given the greater variability of self-reported data, the relatively small sample size, and the short duration of the intervention.

These findings are consistent with earlier clinical trials in which we used this same lifestyle intervention and the same measure of lifestyle index and found significant dose-response correlations between this lifestyle index (i.e., the degree of lifestyle changes) and changes in the degree of coronary atherosclerosis (percent diameter stenosis) in coronary heart disease; [ 41 , 45 ] changes in PSA levels and LNCaP cell growth in men with prostate cancer; [ 42 ] and changes in telomere length [ 43 ].

We also found significant differences between the intervention and control groups in several taxa (groups of micro-organisms) in the microbiome which may be beneficial.

There were no significant differences in depression scores as measured by PHQ-9 between the intervention and control groups. Therefore, reduction in depression is unlikely to account for the overall improvements in cognition and function seen in the intervention group patients.

We also found that substantial lifestyle changes were required to stop the progression of MCI in these patients. In the primary analysis, this ranged from 71.4% adherence for ADAS-Cog to 95.6% adherence for CDR-Global to 120.6% adherence for CDR-SB. In other words, extensive lifestyle changes were required to stop or improve cognition and function in these patients. This helps to explain why other studies of less-intensive lifestyle interventions may not have been sufficient to stop deterioration or improve cognition and function.

For example, comparing these results to those of the MIND-AD clinical trial provides more biological plausibility for both studies [ 44 ]. That is, more moderate multimodal lifestyle changes may slow the rate of worsening of cognition and function in MCI or early dementia due to early-stage AD, whereas more intensive multimodal lifestyle changes may result in overall average improvements in many measures of cognition and function when compared to a randomized usual-care control group in both clinical trials.

Lifestyle changes may provide additional benefits to patients on drug therapy. Anti-amyloid antibodies have shown modest effects on slowing progression, but they are expensive, have potential for adverse events, are not yet widely available, and do not result in overall cognitive improvement [ 40 ]. Perhaps there may be synergy from doing both.

Limitations

This study has several limitations. Only 51 patients were enrolled and randomized in our study, and two of these patients (both in the intervention group) withdrew during the trial. Showing statistically significant differences across different tests of cognition and function and other measures despite the relatively small sample size suggests that the lifestyle intervention may be especially effective and has strong internal validity.

However, the smaller sample size limits generalizability, especially since there was much less racial and ethnic diversity in this sample than we strived to achieve. Also, we measured these differences despite the relative insensitivity of these measures, which might have increased the likelihood of a type II error.

Raters were blinded to the group assignment of the participants. However, unlike a double-blind placebo-controlled drug trial, it is not possible to blind subjects in a lifestyle intervention about whether or not they are receiving the intervention. This might have affected outcome measures, although to reduce positive expectations and because it was true, patients were told during the study that we did not know whether or not this lifestyle intervention would be beneficial, and we said that whatever we showed would be useful.

Also, 20 weeks is a relatively short time for any intervention with MCI or early dementia due to AD. We did not include direct measures of brain structure in this trial, so we cannot determine whether there were direct impacts on markers of brain pathology relevant to AD. However, surrogate markers such as the plasma Aβ42/40 ratio are becoming more widely accepted.

Not all patients in the intervention group improved. Of the 24 patients in the intervention group, 10 showed improvement as measured by the CGIC test, 7 were unchanged, and 7 worsened. In the control group, none improved, 8 were unchanged, and 17 worsened. In part, this may be explained by variations in adherence to the lifestyle intervention, as there was a significant relationship between the degree of lifestyle change and the degree of change in cognition and function across both groups. We hope that further research may further clarify other factors and mechanisms to help explain why cognition and function improved in some patients but not in others.

The findings on the degree of lifestyle change required to stop the worsening or improve cognition and function need to be interpreted with caution. Since data from both groups were combined, it was no longer a randomized trial for this specific analysis, so there could be unknown confounding influences. Also, it is possible that those with improved changes in cognition were better able to adhere to the intervention and thus have higher lifestyle indices.

In summary, in persons with mild cognitive impairment or early dementia due to Alzheimer’s disease, comprehensive lifestyle changes may improve cognition and function in several standard measures after 20 weeks. In contrast, patients in the randomized control group showed overall worsening in all four measures of cognition and function during this time.

The validity of these findings was supported by the observed changes in plasma biomarkers and microbiome; the dose-response correlation of the degree of lifestyle change with the degree of improvement in all four measures of cognition and function; and the correlation between the degree of lifestyle change and the degree of changes in the Aβ42/40 ratio and the changes in some other relevant biomarkers in a beneficial direction.

Our findings also have implications for helping to prevent AD. Newer technologies, some aided by artificial intelligence, enable the probable diagnosis of AD years before it becomes clinically apparent. However, many people do not want to know if they are likely to get AD if they do not believe they can do anything about it. If intensive lifestyle changes may cause improvement in cognition and function in MCI or early dementia due to AD, then it is reasonable to think that these lifestyle changes may also help to prevent MCI or early dementia due to AD. Also, it may take less-extensive lifestyle changes to help prevent AD than to treat it. Other studies cited earlier on the effects of these lifestyle changes on diseases such as coronary heart disease support this conclusion. Clearly, intensive lifestyle changes rather than moderate ones seem to be required to improve cognition and function in those suffering from early-stage AD.

These findings support longer follow-up and larger clinical trials to determine the longer-term outcomes of this intensive lifestyle medicine intervention in larger groups of more diverse AD populations; why some patients beneficially respond to a lifestyle intervention better than others besides differences in adherence; as well as the potential synergy of these lifestyle changes and some drug therapies.

Availability of data and materials

The datasets used and/or analyzed during the current study may be available from the corresponding author on reasonable request. Requesters will be asked to submit a study protocol, including the research question, planned analysis, and data required. The authors will evaluate this plan (i.e., relevance of the research question, suitability of the data, quality of the proposed analysis, planned or ongoing analysis, and other matters) on a case-by-case basis.

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Acknowledgements

We are grateful to each of the following people who made this study possible. Paramount among these are all of the study participants and their spouse or support person. Their commitment was inspiring, and without them this study would not have been possible. Each of the staff who provided and supported this program is exceptionally caring and competent, and includes: Heather Amador, who coordinated and administered all grants and infrastructure; Tandis Alizadeh, who is chief of staff; as well as Lynn Sievers, Nikki Liversedge, Pamela Kimmel, Stacie Dooreck, Antonella Dewell, Stacey Dunn-Emke, Marie Goodell, Emily Dougherty, Kamala Berrio, Kristin Gottesman, Katie Mayers, Dennis Malone, Sarah & Mary Barber, Steven Singleton, Kevin Lane, Laurie Case, Amber O’Neill, Annie DiRocco, Alison Eastwood, Sara Henley, Sousha Naghshineh, Sarah Reinhard, Laura Kandell, Alison Haag, Sinead Lafferty, Haley Perkins, Chase Delaney, Danielle Marquez, Ava Hoffman, Sienna Lopez, and Sophia Gnuse. Dr. Caitlin Moore conducted much of the cognition and function testing along with Dr. Catherine Madison, Trevor Ragas, Andrea Espinosa, Lorraine Martinez, Davor Zink, Jeff Webb, Griffin Duffy, Lauren Sather, and others. Dr. Cecily Jenkins trained the ADAS-Cog rater. Dr. Jan Krumsiek and Dr. Richa Batra performed important analyses in Dr. Rima Kaddurah-Daouk’s lab. Dr. Pia Kivisåkk oversaw biomarker assays in Dr. Steven Arnold's lab. We are grateful to all of the referring neurologists. Board members of the nonprofit Preventive Medicine Research Institute provided invaluable oversight and support, including Henry Groppe, Jenard & Gail Gross, Ken Hubbard, Brock Leach, and Lee Stein, as well as Joel Goldman.

Author’s information

DO is the corresponding author. RT contributed as the senior author.

We are very grateful to Leonard A. Lauder & Judith Glickman Lauder; Gary & Laura Lauder; Howard Fillit and Mark Roithmayr of The Alzheimer’s Drug Discovery Foundation; Mary & Patrick Scanlan of the Mary Bucksbaum Scanlan Family Foundation; Laurene Powell Jobs/Silicon Valley Community Foundation; Pierre & Pamela Omidyar Fund/Silicon Valley Community Foundation (Pat Christen and Jeff Alvord); George Vradenburg Foundation/Us Against Alzheimer’s; American Endowment Foundation (Anna & James McKelvey); Arthur M. Blank Family Foundation/Around the Table Foundation (Elizabeth Brown, Natalie Gilbert, Christian Amica); John Paul & Eloise DeJoria Peace Love & Happiness Foundation (Constance Dykhuizen); Maria Shriver/Women’s Alzheimer’s Movement (Sandy Gleysteen, Laurel Ann Gonsecki, Erin Stein); Mark Pincus Family Fund/Silicon Valley Community Foundation; Christy Walton/Walton Family Foundation; Milken Family Foundation; The Cleveland Clinic Lou Ruvo Center for Brain Health (Larry Ruvo); Jim Greenbaum Foundation; R. Martin Chavez; Wonderful Company Foundation (Stewart & Lynda Resnick); Daniel Socolow; Anthony J. Robbins/Tony Robbins Foundation; John Mackey; John & Lisa Pritzker and the Lisa Stone Pritzker Family Foundation; Ken Hubbard; Greater Houston Community Foundation (Jenard & Gail Gross); Henry Groppe; Brock & Julie Leach Family Charitable Foundation; Bucksbaum/Baum Foundation (Glenn Bucksbaum & April Minnich); YPO Gold Los Angeles; Lisa Holland/Betty Robertson; the Each Foundation (Lionel Shaw); Moby Charitable Fund; California Relief Program; Gary & Lisa Schildhorn; McNabb Foundation (Ricky Rafner); Renaissance Charitable Foumdation (Stephen & Karen Slinkard); Network for Good; Ken & Kim Raisler Foundation; Miner Foundation; Craiglist Charitable Fund (Jim Buckmaster and Annika Joy Quist); Gaurav Kapadia; Healing Works Foundation/Wayne Jonas; and the Center for Innovative Medicine (CIMED) at the Karolinska Institutet, Hjärnfonden, Stockholms Sjukhem, Research Council for Health Working Life and Welfare (FORTE). In-kind donations were received from Alan & Rob Gore of Body Craft Recreation Supply (exercise equipment), Dr. Andrew Abraham of Orgain, Paul Stamets of Fungi Perfecta ( Host Defense Lion’s Mane), Nordic Naturals, and Flora. Dr. Rima Kaddurah-Daouk at Duke is PI of the Alzheimer Gut Microbiome Project (funded by NIA U19AG063744). She also received additional funding from NIA that has enabled her research (U01AG061359 & R01AG081322).

The funders had no role in the conceptualization; study design; data collection; analysis; and interpretation; writing of the report; or the decision to submit for publication.

Author information

Authors and affiliations.

Preventive Medicine Research Institute, 900 Bridgeway, Sausalito, CA, USA

Dean Ornish, Catherine Madison, Anne Ornish, Nancy DeLamarter, Noel Wingers & Carra Richling

University of California, San Francisco and University of California, San Diego, USA

Dean Ornish

Ray Dolby Brain Health Center, California Pacific Medical Center, San Francisco, CA, USA

Catherine Madison

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska vägen 37 A, SE-171 64, Solna, Sweden

Miia Kivipelto

Theme Inflammation and Aging, Karolinska University Hospital, Karolinska vägen 37 A, SE-171 64, Stockholm, Solna, Sweden

The Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, St Mary’s Hospital, Norfolk Place, London, W2 1PG, United Kingdom

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Yliopistonranta 8, 70210, Kuopio, Finland

Clinical Services, Preventive Medicine Research Institute, Bridgeway, Sausalito, CA, 900, USA

Colleen Kemp & Sarah Tranter

Division of Biostatistics, Department of Epidemiology & Biostatistics, UCSF, San Francisco, CA, USA

Charles E. McCulloch

Neurosciences, University of California, San Diego, CA, USA

Douglas Galasko

Clinical Neurology, School of Medicine, University of Nevada, Reno, USA

Renown Health Institute of Neurosciences, Reno, NV, USA

Harvard Medical School, Boston, MA, USA

Dorene Rentz, Rudolph E. Tanzi & Steven E. Arnold

Center for Alzheimer Research and Treatment, Boston, MA, USA

Dorene Rentz

Mass General Brigham Alzheimer Disease Research Center, Boston, MA, USA

Elizabeth Blackburn Lab, UCSF, San Francisco, CA, USA

UCSF, San Francisco, CA, USA

Departments of Medicine and Psychiatry, Duke University Medical Center and Member, Duke Institute of Brain Sciences, Durham, NC, USA

Rima Kaddurah-Daouk

Department of Pediatrics; Department of Computer Science & Engineering; Department of Bioengineering; Center for Microbiome Innovation, Halıcıoğlu Data Science Institute, University of California, San Diego, La Jolla, CA, USA

Department of Pediatrics and Scientific Director, American Gut Project and The Microsetta Initiative, University of California San Diego, La Jolla, CA, USA

Daniel McDonald

Bioinformatics and Systems Biology Program; Rob Knight Lab; Medical Scientist Training Program, University of California, San Diego, La Jolla, CA, USA

Lucas Patel

Buck Institute for Research on Aging, San Francisco, CA, USA

Eric Verdin

University of California, San Francisco, CA, USA

Genetics and Aging Research Unit, Boston, MA, USA

Rudolph E. Tanzi

McCance Center for Brain Health, Boston, MA, USA

Massachusetts General Hospital, Boston, MA, USA

Interdisciplinary Brain Center, Massachusetts General Hospital, Boston, MA, USA

Steven E. Arnold

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Contributions

DO, CM, MK, CK, DG, JA, DR, CEM, JL, KN, AO, ST, ND, NW, CR, RKD, RK, EV, RT, and SEA were involved in the study design and conduct. DO conceptualized the study hypotheses (building on the work of MK), obtained funding, prepared the first draft of the manuscript, and is the principal investigator. CEM oversaw the statistical analyses and interpretation, and DR oversaw the cognition and function testing and interpretation. CK and ST oversaw all clinical operations and patient recruitment, including the IRB. JL conducted the telomere analyses. CM oversaw patient selection. AO developed the learning management system and community platform for patients and providers. KN managed an IRB. ND co-led most of the support groups, and CR oversaw all aspects involving nutrition. All authors participated in writing the manuscript. NW and ST oversaw data collection and prepared the databases other than the microbiome databases which were overseen by RK and prepared by DM and LP who helped design this part of the study. CM, CK, JL, RKD, RK, DM, and LP were involved in the acquisition of data. SA, RT, and RKD did biomarker analyses. All authors contributed to critical review of the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Dean Ornish .

Ethics declarations

Competing interests.

MK is one of the Editors-in-Chief of this journal and has no relevant competing interests and recused herself from the review process. RKD is an inventor on key patents in the field of metabolomics and holds equity in Metabolon, a biotech company in North Carolina. In addition, she holds patents licensed to Chymia LLC and PsyProtix with royalties and ownership. DO and AO have consulted for Sharecare and have received book royalties and lecture honoraria and, with CK, have received equity in Ornish Lifestyle Medicine. RK is a scientific advisory board member and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. DM is a consultant for BiomeSense. RT is a co-founder and equity holder in Hyperion Rx, which produces the flashing-light glasses at a theta frequency of 7.83 Hz used as an optional aid to meditation. The rest of the authors declare that they have no competing interests.

Ethics approval and consent to participate

This clinical trial was approved by the Western Institutional Review Board on 12/31/2017 (approval number: 20172897) and all participants and their study partners provided written informed consent. The trial protocol was also approved by the appropriate Institutional Review Board of all participating sites; and all subjects provided informed consent.

Consent for publication

Informed consent was received from all patients. All data from research participants described in this paper is de-identified.

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Ornish, D., Madison, C., Kivipelto, M. et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: a randomized, controlled clinical trial. Alz Res Therapy 16 , 122 (2024). https://doi.org/10.1186/s13195-024-01482-z

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Received : 21 February 2024

Accepted : 15 May 2024

Published : 07 June 2024

DOI : https://doi.org/10.1186/s13195-024-01482-z

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