Implementing Clinical Trials for the Treatment of Long COVID

The RECOVER Initiative’s Initial Framework for Conducting Clinical Trials

Responding to the Challenge of Long COVID

Since the early days of the COVID-19 pandemic, significant progress has been made in the diagnosis and management of the virus; however, many unknowns remain for what a SARS-CoV-2 infection might mean for an individual in the longer term. In addition to finding solutions to help those diagnosed in the short term, experts have also been searching for answers to help those suffering from symptoms that continue well beyond the initial infection. Long COVID can cause negative health effects for people far past their initial COVID-19 diagnosis and may result in additional health challenges even after recovery from the virus. 

To combat this public health challenge, the National Institutes of Health (NIH) established the Researching COVID to Enhance Recovery (RECOVER) Initiative, which seeks to understand, prevent, and treat Long COVID. To date, no effective drug or nondrug treatments exist for patients suffering from Long COVID, highlighting the need for research to fill this critical gap. 

As part of the RECOVER effort, NIH has launched an adaptive clinical trial platform program called RECOVER-CT. Due to the multiple manifestations of Long COVID, the RECOVER-CT program explores treatments directed at potential underlying disease mechanisms, as well as the Long COVID symptoms themselves, including impaired exercise capacity and musculoskeletal symptoms (e.g., muscle aches, fatigue, breathlessness, physical incapacitation), persistence of systemic inflammation, neurocognitive disfunction, sleep disorders, dysautonomia, and postural orthostatic tachycardia syndrome. These trial platforms are investigating an array of interventions, including cognitive and behavioral, rehabilitation, complementary alternative medicine, drugs, and devices. 

As the Administrative Coordinating Center (ACC) of RECOVER—and in partnership with Duke Clinical Research Institute as the Data Coordinating Center (DCC)—RTI experts have collaborated with NIH and network members to implement the trial program to address the burden of Long COVID.

Administrative Coordinating Center Support for RECOVER-CT Clinical Trials

Governance

The ACC provides operational support to RECOVER-CT governing committees, including critical committees such as the Clinical Trial Steering Committee (CT-SC) and the Data and Safety Monitoring Board (DSMB). The CT-SC aids in the development and optimization of the clinical trial portfolio. This includes providing input on study design, interventions, endpoints, and outcomes, as well as guidance and oversight to ensure that the clinical trials are effectively meeting their scientific objectives and mission. ACC leadership also participates on the CT-SC. The DSMB is an independent group responsible for safeguarding study participants’ interests (e.g., assessing the safety and efficacy of study procedures and data quality).

Operations and Implementation

The ACC includes clinical trial experts who can provide insight and guidance to the trial planning and implementation. Our team collaborates with NIH and the DCC to identify and implement cost-effective best practices for clinical trial activities, including site/vendor identification and selection, recruitment and retention, data quality and management, and analysis.

To better inform clinical research priorities (e.g., intervention selection), the ACC also conducts routine landscape analyses to identify ongoing and completed Long COVID–focused clinical trials. These analyses compile and analyze data from ClinicalTrials.gov, peer-reviewed publications, clinical practice statements, and news articles to provide valuable and actionable insight into evidence available or lacking with respect to potential Long COVID treatments.

Technology and Data

The ACC employs a novel technology infrastructure to support the mission of the RECOVER-CT Program. In particular, the ACC has collaborated with NIH and the DCC to develop and support a private portal that includes role-based access to the following:

• A central hub for RECOVER-CT policies and procedures, document repositories for RECOVER-CT working groups or committees, and site regulatory document and training materials
• An interactive study progress reporting suite that offers near real-time tracking of key performance indicators including contract status; milestone and financial status; site identification, start-up, and activation; enrollment and retention; and data quality and completeness (e.g., visit, primary outcome, mobile health platform data, biospecimens)

The ACC also collaborates with the DCC in the adoption and maintenance of RECOVER common data elements and manages the upload of public use data into BioData Catalyst.

Making a Lasting Impact in COVID-19 Public Health Research

As the ACC, RTI serves as the central hub for managing the function and implementation of RECOVER-CT trials. From providing the governance oversight needed for a multisite program to overseeing the operations of the trials, our team has built the foundation to enable this critical effort. Accomplishments of RECOVER-CT are as follows:

• We have provided expert insight on the regulatory pathway, infectious diseases and other infection-associated chronic conditions (e.g., myalgic encephalomyelitis/chronic fatigue syndrome), community engagement, and clinical trial design and operations.
• Literature reviews have encompassed more than 1,200 unique ClinicalTrials.gov records and 149 peer-reviewed publications, with results routinely disseminated to NIH.
• Over 1,857 members of the program are accessing the private portal, including 51 NIH representatives, 125 DCC operations team members, and 1,585 clinical trial site staff.
• Five platform protocols have been initiated, comprising 8 clinical trials and testing 13 interventions across more than 100 sites using cost-effective/efficient unit-based operational models developed by the ACC in collaboration with the DCC and NIH.
• The first clinical trial completed enrollment in 9 months, and to date, remarkably low rates of treatment and study follow-up discontinuation have been observed across all trials (<5%).

In response to the pandemic, RTI has supported NIH’s efforts to understand and treat COVID-19 and its outcomes. Not only has our multidisciplinary team applied best practices to the RECOVER-CT Program, we have also provided valuable insight as the ACC for the trans-NIH ACTIV Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) portfolio and virtual biorepository, and we are involved in planning and implementing three National Institute of Allergy and Infectious Diseases–funded programs focused on infectious diseases and pandemic preparedness: the Centers for Research in Emerging Infectious Diseases (CREID) Network, the Research and Development of Vaccines and Monoclonal Antibodies for Pandemic Preparedness (ReVAMPP) Network, and the Tropical Medicine Research Centers (TMRC) program.

Using our experience supporting and managing complex research networks and initiatives, RTI has collaborated in the successful development and implementation of the largest national clinical trial research network for investigating treatments for Long COVID. 

Learn more about how RTI’s coordinating center work has impacted public health.