Insurers falling seriously short in mental health, substance use disorder benefits, feds say

 Health insurers are failing to deliver parity in mental health and substance use disorder benefits for their members, despite laws on the books designated to ensure equal coverage, according to a new report issued by HHS and the Labor and Treasury departments on Tuesday.

The Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA) requires that the financial requirements and treatment limitations, such as copayments or prior authorization requirements, that payers impose on mental health or substance use disorder benefits can't be more restrictive than those on all other medical or surgical benefits. According to the law, group health plan or health insurance issuers aren't allowed to impose such non-quantitative treatment limitations (NQTLs) on mental health or substance use disorder benefits, unless it's comparable to other benefits.

Though progress has been made, NQTLs on mental health and substance use disorder benefits are still pervasive in the health insurance system — not as an oversight, but a decision, Acting Assistant Secretary for Employee Benefits Security Ali Khawar said.

"Personally, I'm pretty confused about why the level of compliance so long after the statute has passed and after so much guidance has been issued is as poor as it is," Khawar told reporters on a Tuesday call, though the acting Employee Benefits Security Administration head said he wasn't going to subscribe any motivation to it.

"We want to get to a place where compliance is the norm. And unfortunately that’s not the place we’re in right now," Khawar said.

Federal agencies have been ramping up compliance efforts across multiple administrations, though COVID-19 has thrown disparities in health access into sharp relief and made health equity a key prong of the Biden administration's agenda.

The Department of Labor's EBSA is a big part of this, having primary enforcement jurisdiction over MHPAEA for about 2 million health plans covering roughly 136 million Americans. CMS has also increased its MHPAEA enforcement activities in the individual and fully insured group markets in states where it has authority, and over non-federal governmental plans in all states (such as plans for employees of state and local governments).

The Consolidated Appropriations Act passed last year also gave the departments a new tool in enforcing MHPAEA, along with additional funding to implement it. CAA also required the departments to report their findings to Congress under the new provision.

The new enforcement tool expressly requires group health plans and health insurance issuers to document how they design and apply NQTLs. If after an analysis, regulators determine the plan is noncompliant with MHPAEA, they can call out the payer in their annual report to Congress, of which this is the first.

Regulators found widespread noncompliance with EBSA following a slew of investigations.

Since kicking off the process last year, EBSA has issued 156 letters to plans requesting NQTL analyses, while CMS has issued 15.

None of the initial comparative analyses received to date have been sufficient, the departments said. Among other shortcomings, plans have submitted analyses lacking supporting evidence or explanation or failing to identify specific benefits affected by an NQTL.

Additionally, many insurers said they were unprepared for the government's request for the analysis, despite MHPAEA's requirement they track and document the information for more than a decade.

That resulted in a flurry of followups from EBSA and CMS requesting additional information and calling out deficiencies in the original reports.

After receiving more information, so far EBSA has issued 30 initial determination letters finding plans were imposing NQTLs on mental health and substance use disorders lacking parity with medical or surgical benefits, while CMS has issued 15.

Regulators found a spate of common issues, including plans limiting or excluding applied behavioral analysis or other treatment for autism spectrum disorder; issuers requiring licensed mental health or substance use providers to bill the plan only through specific types of other providers; or limiting or excluding medication assisted treatment for opioid use disorder.

Some plans were also covering nutritional counseling for medical conditions like diabetes, but not for mental health conditions like anorexia, bulimia or binge-eating disorder.

Alerting the plans did lead to some increasing benefits, according to the report.

In response to the initial determination letters, EBSA received corrective action plans from 19 insurers, while CMS received six.

So far, 26 plans and issuers have agreed to make prospective changes to their benefits, as of the end of October. Those include the complete removal of an NQTL limiting mental health or substance use benefits, or adding previously excluded coverage for such benefits.

In one example, EBSA discovered a large service provider administering claims for hundreds of self-funded plans nationwide was excluding applied behavior analysis for children with autism. Applied behavior analysis, a treatment delivered by a behavioral specialist multiple times a week over the course of months, is a primary early therapy for autism and has been shown to improve development.

After identifying plans administered by that provider, EBSA requested the plans perform comparative analyses and found many were noncompliant.

So far, three plans that ran the analyses for the applied behavior analysis exclusion have decided to remove the exclusion in the future, and will now cover the therapy for children with autism. That correction affects more than 18,000 plan members, EBSA said.

No specific noncompliant plans were named in the report. Khawar said the government is either still engaging with them or they've corrected the problem.

But if noncompliant plans don't fix their arrangements, they'll receive a final termination of noncompliance which would make them notify their participants and beneficiaries that they’re not in compliance.

They'll also be named in the next report to Congress.

Access to mental health and substance use disorder treatment was a huge issue even before the pandemic, with the conditions facing stigma, discrimination and administrative barriers to care not faced by other patients.

Though the pandemic has greatly exacerbated conditions like anxiety and depression, mental illness was widespread in the U.S. even before COVID-19. Almost 52 million adults experienced some form of mental illness in 2019, according to the National Institute of Mental Health.

But now, with the pandemic, such benefits are needed like never before, regulators said.

"Especially in the midst of the pandemic when we've seen so much social isolation and so many health inequities really being laid bare, the importance of these issues has really come to the forefront," Khawar said.

Substance use disorders have also worsened during COVID-19. From April 2020 to April 2021, already rising overdose figures skyrocketed. More than 100,000 Americans died of overdose during that period, a figure representing a nearly 30% year-over-year increase, according to data from the Centers for Disease Control and Prevention.

Though the federal government is stepping up oversight of plans to ensure coverage parity, the Labor and Health departments could have more power, according to the report.

For one, EBSA noted additional civil monetary penalty authority for any plans not complying with MHPAEA would be "quite helpful," Khawar said.

https://www.healthcaredive.com/news/health-insurers-mental-health-substance-use-coverage-hhs-labor-parity/617664/

Hospitals request more federal help battling rising labor expenses, staffing shortages amid omicron

 Almost two years after the pandemic began in the U.S., hospitals are grappling with some of their most dire staffing shortages yet.

Among hospitals reporting staffing data to the federal government, 31% said they were anticipating a critical staffing shortage this past week, and 12 states had 40% or more of their hospitals reporting critical staffing shortages, according to the HHS.

Widespread stress and burnout are helping to drive the labor shortage, spurring nurses in particular to quit their roles. In addition, higher wages from travel-staffing agencies are enticing nurses to leave permanent roles for temporary positions.

With hospitals facing persistent, heightened labor expenses while tackling the omicron variant, they're asking for more federal help, including more funding in the Provider Relief Fund and for remaining funds to be distributed as Congress looks to pass the fiscal year 2022 appropriations bill before funding runs out Feb. 18, hospital leaders said during an American Hospital Association call with reporters Tuesday.

The hospital lobby also is renewing its push in requesting the Federal Trade Commission to investigate travel-nurse staffing firms for anticompetitive behavior as dwindling supplies of available nurses have led to elevated pay rates throughout the pandemic.

"These companies have exploited the severe shortage of healthcare personnel during the pandemic by charging exorbitant rates, often times two to three times pre-pandemic amounts," AHA CEO Rick Pollack said on the call.

From January 2020 to this month, advertised pay rates for travel nurses have jumped 67%, with hospitals billed an additional 28% to 32% over those pay rates by staffing firms, according to Proculent Health, a workforce data and technology company. In some areas, travel-nurse pay rates have been as high as $240 an hour or more.

In turn, hospital labor expenses are above pre-pandemic levels, up 12% on an absolute basis and 19.5% on a per adjusted discharge basis compared with 2019, according to a report from Kaufman Hall.

Shortages particularly are acute in rural areas, especially for certain workers such as respiratory therapists.

West Tennessee Healthcare's Bolivar and Camden Hospitals lost more than half of their respiratory therapists throughout the pandemic with many leaving to work for traveling staffing agencies, Ruby Kirby, the CEO of the facilities, said on Tuesday's AHA call.

"We cannot compete with the salaries that they're offering," Kirby said.

Some states have enlisted National Guard members to assist understaffed healthcare facilities amid surges, though smaller, rural systems like Kirby's often don't meet the volume threshold to apply for those resources, she said.

Kirby estimated most rural hospitals likely are experiencing a 30% to 50% vacancy rate across all roles.

Hospitals are busier than ever, unlike the first days of the pandemic when stay-at-home measures and restrictions on elective care to free up hospital resources were in place.

Other care has since returned and higher-acuity patients are staying longer in the hospital. Average length of stay has risen 8.8% compared with pre-pandemic levels, and climbed 9.5% from October to November of 2021 alone, according to data from Kaufman Hall.

Henry Ford Health System in Detroit had about 75 beds closed due to staffing concerns across its nine-hospital system Tuesday, CEO Wright Lassiter said, though that's an improvement from 30 days ago when it had 150 beds closed.

Staffing shortages also caused the system to delay about 400 procedures over the past month, Lassiter said.

In a Thursday letter, AHA asked Congress to include in legislation measures to quickly disperse remaining money from the Provider Relief Fund while adding $25 billion to help hospitals deal with staffing shortages and heightened labor expenses.

The HHS most recently funneled $9 billion from the Provider Relief fund in December to more than 69,000 providers in all 50 states, with average payments ranging from $58,000 for small providers to $1.7 million for large providers, according to the agency. 

AHA also is asking for a Medicare sequester relief extension, more time for hospitals to repay accelerated and advance Medicare payments and greater relief for some 340B hospitals so they can stay eligible for the program, according to the letter.

In addition, the lobby asked the FTC to investigate nurse-staffing agencies for anticompetitive pricing in February, though it hasn't yet gotten a response, Pollack said.

"That's why we're asking the administration to help us ensure this matter gets the attention it needs to protect these agencies from exploiting hospitals and health systems' financial viability at a time when they can least afford it," he said.

https://www.healthcaredive.com/news/omicron-hospital-staffing-shortages-AHA-Congress-travel-nurse-FTC/617699/

Safety net hospitals report growing financial hit from loss of 340B drug discounts

 

• The number of drug companies restricting discounted pricing for hospitals in the 340B drug discount program has steadily increased despite government warnings that practice violates the law, stressing the finances of safety net hospitals, according to a new report from hospital association 340B Health.
• Large, mostly urban facilities have lost 23% of the savings they used to get from 340B discounts through partnerships with community pharmacies, according to the survey of 510 hospitals. For critical access hospitals (rural hospitals with up to 25 beds that are the only hospitals within 10 miles of another provider), the losses averaged 39%.
• Drugmakers' ability to restrict 340B discounts is currently being litigated in court. But at the time of the survey — November and December 2021 —  only eight of the 12 drug companies that are now limiting 340B pricing had those policies in place, so it likely underestimates hospital losses, the group, which represents some 1,400 U.S. safety net hospitals, said.

The 340B drug discount program enacted almost three decades ago requires drug companies that want to participate in Medicaid and Medicare's drug benefit to agree to charge no more than the statutory ceiling prices for eligible outpatient drugs.

Hospitals and clinics then use the savings from those discounts to care for low-income patients and rural communities, without having to rely on taxpayer dollars. But the program has faced criticism for lax oversight from pharmaceutical manufacturers and lawmakers, given hospitals don't have to account for how they use the savings.

340B providers get discounts for the drugs they dispense to eligible patients, along with those dispensed to their patients by contracted community pharmacies. Discounts on drugs dispensed at community pharmacies make up about a quarter of hospitals' overall 340B savings, and more than half of savings for critical access hospitals.

That makes the loss of discounts from community pharmacies they contract with — the avenue most restricted by drugmakers — particularly acute, 340B Health said.

Large facilities reported a median loss of $1 million from the pared-back savings, while a tenth of the hospitals reported losses of $9 million or more. But the impact is heightened on small, rural providers like critical access hospitals, where the 39% average loss evens out to about $220,000 per CAH. A tenth of those facilities lost $700,000 or more.

Loss of those funds can have a significant impact on safety net hospitals already operating under razor-thin margins. Hospitals might be forced to reduce programs and services or eliminate them altogether, cut jobs for people providing the services and even close doors, the report said.

That's bad for vulnerable populations: According to 340B, hospitals in the program provide 60% of all uncompensated care in the U.S. and 75% of all hospital care to Medicaid patients.

Pharmaceutical manufacturers with existing or planned community pharmacy limits are Eli Lilly, Sanofi, AstraZeneca, Novo Nordisk, Novartis, Amgen, Bristol Myers Squibb, Merck, AbbVie, United Therapeutics, UCB and Boehringer Ingelheim.

"These figures are only the tip of a very dangerous iceberg," 340B CEO Maureen Testoni said in a statement on the report. "These unlawful actions are weakening the health care safety net and pose a threat to patients. They must stop."

Powerful pharmaceutical lobby PhRMA said the report emphasizes the need for greater transparency in 340B, and that hospitals receiving discounts from contract pharmacies was never authorized by Congress and may not result in patients sharing in the savings.

PhRMA also pointed to the report's limitations, noting the 510 hospitals surveyed represent only a small portion of the 2,600 hospitals participating in 340B, and it may not be a representative sample.

"There are no requirements that hospitals report how they use the savings they generate from 340B, which leaves the government, manufacturers and patients left to take 340B hospitals at their word with no proof points. This report appears to be a carefully curated look at a subset of 340B hospitals, not a clear look at how all 340B hospitals use 340B," a spokesperson told Healthcare Dive.

Eli Lilly was the first drug company to impose restrictions in July 2020, kicking off a domino effect among its peers. Some stopped giving the 340B ceiling price on their drugs sold to the providers and dispensed through contract pharmacies, while others limited sales by selling products only after a covered entity demonstrated 340B compliance or released specific data.

Pharmaceutical companies defend the restrictions by arguing the 340B program drives patient costs higher in the long run and that there's no guarantee hospital savings are being invested in patient care. Lobbying group PhRMA has pushed for more oversight into how the savings are spent, pointing to evidence that (among other things) poor oversight may allow the discounts to be received twice for the same drug.

Claims 340B actually increases spending, however, are mostly unsupported by outside research.

But that hasn't stopped some drugmakers from trying to dodge the discounts, which can range from 25% to 50% of the drugs' cost, cutting into profits.

More than 700 drug companies currently participate in 340B, so the 12 drugmakers currently looking to sidestep the drug discount program are a small minority, though they include some of the biggest pharmaceutical companies operating in the U.S.

The Health Resources and Services Administration, which oversees 340B, has notified some manufacturers that they're acting illegally and ordered them to restore 340B pricing and refund overchanges. HRSA has referred six cases to HHS' Office of the Inspector General to consider imposing fines, which could total more than $5,000 per violation if approved.

However, a number of the drugmakers have gone to court to try to block HHS. To date, two district courts in the states of Indiana and New Jersey have ruled in favor of HRSA, while a third court in Washington, D.C., said HRSA's position that pharmaceutical manufacturers can't limit 340B discounts isn't the only possible reading of the law, deciding in favor of the drug companies.

Those three district court decisions are currently pending appeals, while another in Delaware district court has not yet issued a decision.

Drugmakers, hospitals and the government are also fighting over a rule HHS finalized in December 2020 on how hospitals and drugmakers handle 340B disputes. The rule would create a dispute resolution mechanism for hospitals if they believe they were overcharged for 340B medications by at least $35,000. Drug companies can also appeal if they think a provider received duplicative discounts.

Neither providers nor pharma companies liked the rule, with drugmakers arguing the Biden administration didn't follow rulemaking requirements and promulgated the rule due to political pressure from Congress to lower drug prices. Meanwhile, providers said it was insufficient to address drug companies' attacks on 340B.

Eli Lilly filed a suit seeking to stop the rule, and a federal judge granted its request early 2021.

Another piece of 340B litigation has wound its way up to the Supreme Court over Trump-era cuts to 340B drugs dispensed through off-campus hospital outpatient sites.

The American Hospital Association, the American Association of Medical Colleges, America's Essential Hospitals and three freestanding hospitals sued not long after the rule was implemented. The Supreme Court heard arguments in December, and a decision is expected sometime this summer.

https://www.healthcaredive.com/news/safety-net-hospitals-financial-hit-340b-drug-discount-pharma/617844/

Most doctors compensated for volume, not value of care

 

• Most physicians in group practices owned by health systems are paid based on the volume of care they provide rather than value, despite payer efforts to move toward more value-based care, according to a study published Friday by the nonprofit Rand Corporation and published in JAMA Health Forum.
• Volume-based compensation was the most common type of base pay for more than 80% of primary-care doctors and more than 90% of specialists at medical practices owned by health systems, according to a survey conducted between November 2017 and July 2019.
• Systems still used financial incentives for quality and cost performance measures, but the percentage of total physician compensation based on quality and cost was just 9% for primary-care providers and 5% for specialists, according to Rand.

Public and private payers in recent years have pushed for payment reforms encouraging providers to improve care quality and slow spending growth by making care more value based. Still, physicians overall still are paid primarily based on volume rather than the quality and value of healthcare services provided, according to the Rand study.

"The payment systems that are most-often in place are designed to maximize health system revenue by incentivizing providers within the system to deliver more services," Rachel Reid, the study's lead author and a physician policy researcher at Rand, said in a statement.

Researchers examined physician payment structures used in 31 physician organizations affiliated with 22 health systems located in four states. They also interviewed physician organization leaders and surveyed practices to characterize compensation arrangements for both primary care and specialty physicians.

Physicians most commonly reported increasing the volume of services performed as a way to increase their compensation, with about 70% of practices following those plans, and in those cases, incentives based on volume accounted for more than two-thirds of their compensation.

While incentives based on clinical quality, cost, patient experience and access to care also were commonly included in physician pay, those payments represented a small fraction of doctors' total compensation and are "likely to only marginally affect physician behavior," the study said.

"For the U.S. healthcare system to truly realize the potential of value-based payment reform and deliver better value for patients, health systems and provider organizations will likely need to evolve the way that frontline physicians are paid to better align with value," Reid said.

https://www.healthcaredive.com/news/doctors-paid-for-volume-not-value-based-care-RAND-JAMA-physician-compensation/617911/

Identifying Patients With COVID-19 Who May Benefit From Convalescent Plasma

 Hyung Park, PhD¹; Thaddeus Tarpey, PhD¹; Mengling Liu, PhD^1,2; et a

doi:10.1001/jamanetworkopen.2021.47375

PDF: https://scholar.google.com/scholar_url?url=https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2788376/park_2022_oi_211304_1642537124.07286.pdf&hl=en&sa=T&oi=ucasa&ct=ufr&ei=o770YYKzEIjGmwHTnpfQDw&scisig=AAGBfm1HQAt3UmROYNSXjmEzKMuZ-jGaiQ

Key Points

Question  What patient characteristics are associated with benefit from treatment with COVID-19 convalescent plasma (CCP)?

Findings  This prognostic study of 2287 patients hospitalized with COVID-19 identified a combination of baseline characteristics that predict a gradation of benefit from CCP compared with treatment without CCP. Preexisting health conditions (diabetes, cardiovascular and pulmonary diseases), blood type A or AB, and earlier stage of COVID-19 were associated with a larger treatment benefit.

Meaning  These findings suggest that simple patient information collected at hospitalization can be used to guide CCP treatment decisions for patients with COVID-19.

Abstract

Importance  Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact.

Objective  To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients’ baseline characteristics.

Design, Setting, and Participants  This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants).

Exposure  Receipt of CCP.

Main Outcomes and Measures  World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI.

Results  A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs.

Conclusions and Relevance  The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788376

Homologous and Heterologous Covid-19 Booster Vaccinations

 

Robert L. Atmar, M.D., 

Kirsten E. Lyke, M.D., 

Meagan E. Deming, M.D., Ph.D., 

Lisa A. Jackson, M.D., M.P.H., 

Angela R. Branche, M.D., 

Hana M. El Sahly, M.D., 

Christina A. Rostad, M.D., 

Judith M. Martin, M.D., 

Christine Johnston, M.D., M.P.H., 

Richard E. Rupp, M.D., 

Mark J. Mulligan, M.D., 

Rebecca C. Brady, M.D., 

 for the DMID 21-0012 Study Group*

DOI: 10.1056/NEJMoa2116414

PDF: 

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2116414?articleTools=true

Abstract

BACKGROUND

Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients.

METHODS

In this phase 1–2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 μg, Ad26.COV2.S (Johnson & Johnson–Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer–BioNTech) at a dose of 30 μg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29.

RESULTS

Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients.

CONCLUSIONS

Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209. opens in new tab.)

https://www.nejm.org/doi/full/10.1056/NEJMoa2116414