PCORI Biweekly COVID-19 Scan: Adaptive Platform Trials, Nirmatrelvir Plus Ritonavir (October 27-November 9, 2022)
Briefing
The Briefing provides an at-a-glance view of some important developments in the information universe surrounding COVID-19. The views presented here are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders.
Bivalent boosters are beginning to show evidence for their anticipated efficacy against Omicron COVID-19 variants. In early November, Pfizer and BioNTech announced clinical data supporting an improved immune response against Omicron BA.4/BA.5 relative to the original vaccine formulation. A recent preprint of laboratory assessments showed the bivalent vaccine’s potential against BA2.75.5 and BQ1.1, as well.
Vaccination might reduce the risk of post-COVID conditions (PCC, also known as long COVID). Surveyed patients across all 50 states and the District of Columbia were less likely to report PCC symptoms if infected after completing the full original vaccination series. Nonetheless, 15 percent of those surveyed had enduring PCC symptoms at least 2 months after their SARS-CoV-2 infections.
This and other estimates of PCC prevalence (see below) demonstrate the size of the need for care. The Department of Veterans Affairs (VA) aimed to see what that care looks like in its health system. The health records of 200 randomly selected veterans revealed that the diagnosis and management of their PCC is characterized by clinical uncertainty and care fragmentation.
Both studies demonstrate the limitations of qualitative research, but also highlight the need for new treatments and innovative ways to test them (see Topics to Watch).
ECRI Horizon Scanning has selected the topics below as those with potential for impact relative to COVID-19 in the United States within the next 12 months. All views presented are preliminary and based on readily available information at the time of writing.
Because these topics are rapidly developing, we cannot guarantee the accuracy of this information after the date listed on this publication. In addition, all views expressed in the commentary section are solely those of ECRI Horizon Scanning and have not been vetted by other stakeholders. Topics are listed in alphabetical order.
Adaptive Platform Trials to Accelerate the Development of Effective Treatments for COVID-19 and Post-COVID Conditions
At a Glance
- Adaptive platform trials (APTs) simultaneously investigate multiple interventions under a shared study protocol and are designed to quickly adapt as new evidence becomes available.
- APT methodology could help identify effective treatments faster and with fewer resources than traditional randomized controlled trials (RCTs).
- The urgent need for rapid evidence generation and dissemination of effective treatments during the COVID-19 pandemic markedly increased the use of APT methodology compared with historical levels. Even before the COVID-19 pandemic, APTs were gaining traction to evaluate emerging population health and health system needs.
- Multiple APTs are ongoing, both nationally and internationally, to investigate treatments for acute COVID-19 and post-COVID conditions (PCC). This methodology may help effective treatments reach patients sooner than via traditional RCTs.
Description
Adaptive platform trials (APTs) are a type of RCT that simultaneously investigate multiple interventions for a disease or condition under a single study protocol, in a perpetual manner. APTs can minimize downtime between trials and accelerate research by adding or removing treatments as new evidence becomes available. Compared with traditional 2-arm trials, APTs require fewer patients, allow quicker treatment evaluation, and have greater power to identify effective therapies.
These APTs have surged in usage during the COVID-19 pandemic because of the urgent need for rapid evidence generation and dissemination of effective treatments. Multiple APTs investigating treatments for COVID-19 have provided evidence to support clinical guidance. These include the phase 2 trial, I-SPY COVID-19 (Quantum Leap Healthcare Collaborative), the phase 3 trial, RECOVERY (RECOVERY Collaborative Group), and the phase 4 trial, OPTIMISE-C19 (University of Pittsburgh).
In October 2022, the National Institutes of Health’s RECOVER initiative, in collaboration with Duke Clinical Research Institute, announced the initiation of a phase 3 APT trial to evaluate treatments for PCC. In September 2022, the Long COVID Research Initiative announced plans to launch a privately-funded platform trial to supplement the work of the RECOVER initiative. Additional APTs for PCC are ongoing in Canada, the United Kingdom, and Europe.
Commentary
APTs efficiently compare multiple treatments against the same control group to identify those most effective at improving health outcomes for patients with COVID-19 and PCC.
Early feedback from ECRI internal stakeholders suggested that APT methodology offers multiple benefits over 2-armed RCT design and might accelerate the identification of effective treatments. With one shared control arm, more patients can receive experimental therapies, and new treatments can be seamlessly added and removed over time. These advantages should be welcomed, because effective therapies are needed to improve patient health outcomes, decrease health care costs, and reduce burden on physicians managing patients with COVID-19 and PCC.
Stakeholders expressed concerns regarding data management, including heightened patient privacy challenges, and evolving data security regulations. Also, because the underlying mechanisms of PCC are incompletely understood, potentially heterogeneous, and vary in clinical presentation, stakeholders suggested investigators utilizing adaptive trials might still find it difficult to compare between treatment groups. Confirmatory trials might still be needed for full regulatory approval.
- Category: Systems and management
- Areas of potential impact: Population health outcomes, health care costs, health care disparities, health care delivery and process
Nirmatrelvir Plus Ritonavir (Paxlovid) to Treat Post-COVID Conditions
At a Glance
- No medications are currently authorized or approved to treat millions of adults in the United States living with post-COVID conditions (PCC), which can encompass a broad range of potentially debilitating symptoms that persist after acute SARS-CoV-2 infection.
- Paxlovid is an oral combination of the antiviral drugs nirmatrelvir and ritonavir. It was previously authorized by the FDA to treat acute COVID-19 in high-risk patients, after a clinical trial demonstrated it reduced the risk of hospitalization and death by 89%.
- Paxlovid is now being investigated to treat adults with PCC. Research suggests that it might improve PCC symptoms by clearing persistent viral infection and reducing inflammation associated with chronic immune activation.
- The National Institutes of Health is investigating the use of Paxlovid to improve PCC symptoms in a phase 3 clinical trial expected to be completed in January 2024.
- A 15-day course of Paxlovid for treating PCC is expected to cost about $1590.
Description
An estimated 7.5 percent of adults in the United States currently have PCC, a broad range of new and worsening symptoms that may persist months, or even years, after SARS-CoV-2 infection. Currently, no medications are authorized or approved to treat PCC.
Paxlovid (copackaged nirmatrelvir plus ritonavir) is an oral antiviral therapy being investigated to treat adults who have PCC. When taken as authorized to treat acute COVID-19 Paxlovid was shown in a preprint study to reduce the risk of developing PCC, regardless of vaccination status or history of prior infection. A growing body of evidence suggests that persistent viral infection and inflammation associated with chronic immune activation contribute to PCC symptoms. Therefore, by inhibiting replication of lingering SARS-CoV-2 virus, Paxlovid might improve symptoms of patients experiencing PCC.
Paxlovid is the first therapy in the United States being investigated to treat PCC as part of the National Institutes of Health RECOVER Initiative’s adaptive platform trial. Investigators at the Duke Clinical Research Institute (Durham, North Carolina) are now conducting a phase 3 clinical trial enrolling 1700 adults suspected or confirmed to have been infected with SARS-CoV-2 and have shown evidence of at least one moderate cluster-associated symptom of PCC occurring more than 4 weeks after acute illness that had persisted for at least 8 weeks. Participants will be randomly assigned to Paxlovid (300 mg nirmatrelvir in two 150 mg tablets and 100 mg ritonavir in one 100 mg tablet) or placebo for 15 days. The trial’s primary completion is expected in January 2024.
A 5-day course of Paxlovid to treat acute COVID-19 is $530; therefore, a 15-day course for PCC could cost about $1590.
Commentary
A significant unmet need exists for effective therapies to treat millions of adults in the United States currently experiencing PCC.
Early feedback from ECRI internal stakeholders suggested Paxlovid might reduce or eliminate PCC symptoms thought to stem from persistent viral infection. An effective treatment for PCC could have extensive health and economic benefits, including improved quality of life, return to normal daily activities, and reduced long-term health care costs. However, Paxlovid may not be effective against symptoms caused by mechanisms other than active viral replication, including immune dysfunction, hypercoagulability, and organ damage.
Additional data are needed, but if effective at improving PCC symptoms, broad diffusion of Paxlovid is likely to be rapid. Paxlovid is a convenient outpatient treatment that physicians are familiar with and is widely available at pharmacies. However, if not reimbursed, the cost might be a financial burden for some patients, hindering diffusion and increasing disparities in access to health care.
- Category: Treatment
- Areas of potential impact: Patient outcomes, health care disparities, health care costs
Horizon scanning is a systematic process that serves as an early warning system to inform decision makers about possible future opportunities and threats. Health care horizon scanning identifies technologies, innovations, and trends with potential to cause future shifts or disruptions—positive or negative—in areas such as access to care, care delivery processes, care setting, costs of care, current treatment models or paradigms, health disparities, health care infrastructure, public health, and patient health outcomes.
The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning to better inform its patient-centered outcomes research investments. Initially, PCORI defined the HCHSS project scope to focus on interventions with high potential for disruption in the United States in 5 priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health conditions, and rare diseases. In addition, the system captures high-level disruptive trends across all clinical areas, which may lead PCORI to expand the project scope to include other priority areas in the future.
In early 2020, the COVID-19 pandemic created a fast-moving, widespread public health crisis. In May 2020, PCORI expanded its HCHSS to elucidate the landscape of potentially impactful applications for COVID-19. The HCHSS COVID-19 supplement scans for, identifies, monitors, and reports on emerging and available COVID-19-related treatments, diagnostics, preventive measures, management strategies, and systems changes with potential for high impact to patient outcomes—for individuals and populations—in the United States in the next 12 months.
The HCHSS COVID-19 supplement produces 3 main outputs:
- Biweekly COVID-19 Scans (eg, this document) provide ECRI Horizon Scanning with a vehicle to inform PCORI and the public in a timely manner of important topics of interest identified during ongoing scanning and topic identification or through the ECRI stakeholder survey process.
- Status Reports (quarterly) briefly list and describe all COVID-19-related topics identified, monitored, and recently archived.
- High Impact Reports (every 4 months) highlight those topics that ECRI internal stakeholders (eg, physicians, nurses, allied health professionals, public health professionals, first responders, health systems experts, clinical engineers, researchers, business and finance professionals, and information technology professionals) have identified as having potential for high impact relative to COVID-19 in the United States.
In May 2021, the COVID-19 supplement was modified and merged with the HCHSS. The Biweekly COVID-19 Scans continue, while the Status Reports and High Impact Reports were folded into the PCORI Horizon Scanning Database and High Potential Disruption Reports.
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Commentary in this COVID-19 Scan reflects preliminary views of ECRI Horizon Scanning and internal ECRI stakeholders.
The information contained in this document has not been vetted by other stakeholders.
We welcome your comments on this Scan. Send them by email to [email protected].
Posted: November 17, 2022
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