Convalescent Plasma Therapy Clinical Effect in Severe COVID-19

Key Points
Question  What is the effect of convalescent plasma therapy added to standard treatment, compared with standard treatment alone, on clinical outcomes in patients with severe or life-threatening coronavirus disease 2019 (COVID-19)?
Finding  In this randomized clinical trial that included 103 patients and was terminated early, the hazard ratio for time to clinical improvement within 28 days in the convalescent plasma group vs the standard treatment group was 1.40 and was not statistically significant.
Meaning  Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not significantly improve the time to clinical improvement within 28 days, although the trial was terminated early and may have been underpowered to detect a clinically important difference.

Abstract

Importance  Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed.
Objective  To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19.
Design, Setting, and Participants  Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled.
Intervention  Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity.
Main Outcomes and Measures  Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours.
Results  Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, −10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.65 [95% CI, 0.29-1.46]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.93]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care.
Conclusion and Relevance  Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference.

Ling Li, MD, PhD^1,2; Wei Zhang, MD^3,4; Yu Hu, MD, PhD⁵; et al Xunliang Tong, MD, PhD⁶; Shangen Zheng, MD⁷; Juntao Yang, PhD⁸; Yujie Kong, MD^1,2; Lili Ren, PhD^9,10; Qing Wei, MD¹¹; Heng Mei, MD, PhD⁵; Caiying Hu, MD¹²; Cuihua Tao, MD^13,14; Ru Yang, MD¹⁵; Jue Wang, MD^1,2; Yongpei Yu, PhD¹⁶; Yong Guo, PhD¹⁷; Xiaoxiong Wu, MD¹⁸; Zhihua Xu, MD^12,19; Li Zeng, MD^3,20; Nian Xiong, MD^12,21; Lifeng Chen, MD²²; Juan Wang, MD¹¹; Ning Man, MD²³; Yu Liu, PhD¹; Haixia Xu, MD^1,2; E. Deng, MS¹; Xuejun Zhang, MS¹; Chenyue Li, MD^1,2; Conghui Wang, PhD⁹; Shisheng Su, PhD¹⁷; Linqi Zhang, PhD²⁴; Jianwei Wang, PhD^9,10; Yanyun Wu, MD, PhD²⁵; Zhong Liu, MD, PhD^1,2

Author Affiliations

JAMA. Published online June 3, 2020. doi:10.1001/jama.2020.10044

https://jamanetwork.com/journals/jama/article-abstract/2766943

LabCorp Launches Website to Connect Patients with COVID-19 Clinical Trials

Laboratory Corporation of America Holdings, or LabCorp, is one of the two largest clinical diagnostic laboratory companies in the U.S. The company announced its Covance drug development business was launching COVID-19 Clinical Trial Connect in the U.S. to help people find information on taking part in clinical trials related to COVID-19.
The site specifically notes five categories of potential participation: if you have been exposed to a confirmed case of COVID-19; if you are experiencing COVID-19 symptoms; if you have been diagnosed with COVID-19; if you have recovered from a confirmed case of COVID-19 infection; and if you are healthy or have interest in vaccine research studies.
“Our goal is to link people interested in these clinical trials with sponsors so that together we may find solutions for this global pandemic,” said Michael Brooks, Covance’s president of Clinical Development and Commercialization Solutions.
The Clinical Trial Connect site can notify potential trial participants of studies run by Covance for the drug industry, as well as studies included in clinicaltrials.gov, the government’s database of privately and publicly funded clinical studies. If patients are interested, they can register on the site.
“With our COVID-19 Clinical Trial Connect, we’re helping bridge the gap,” Brooks added. “Patients who choose to participate in a clinical trial are true medical heroes. We are thrilled to have the capacity to directly engage with patients who would not otherwise be aware of ongoing trials and give them the opportunity to consider participation, particularly at this time.”
LabCorp has more than 65,000 employees and rakes in about $11.5 billion annually. Covance is a global contract research organization (CRO).
LabCorp also announced that it is partnering with digital clinical trial software maker Medable to allow clinical trial participants to engage with trials remotely. This is expected to help with remote data collection, patient engagement and easier app access for trials.
Business Insider noted, “Covance is one of the largest CRO’s globally—and its increased focus on digital trials could be significant in helping LabCorp reduce participant churn amid the pandemic. Social distancing recommendations resulting from the coronavirus pandemic have placed a number of clinical trials on pause—which is leading to participant attrition.”
The adoption of digital access and remote approaches to clinical trials is picking up steam. In early June 2019, the U.S. Food and Drug Administration (FDA) issued a draft guidance on improving the diversity of patient populations in clinical trials. The biggest focus was on getting sponsor companies to include more historically underserved populations in trials, including women, the elderly and minorities. Part of the 18-page guidance included recommendations on remote access.
The guidance stated: “Reduce the frequency of study visits to those needed to appropriately monitor safety and efficacy and consider whether flexibility in visit windows is possible and whether electronic communication (e.g., telephone/mobile telephone, secured electronic mail, social media platforms) or mobile technology tools can be used to replace site visits and provide investigators with real-time data.”
LabCorp, and its biggest competitor, Quest Diagnostics, announced return-to-work services for employers recently. On May 14, LabCorp indicated it would offer staffers check-in health questionnaires, temperature screens and on-site and off-site COVID-19 test collection.
Quest, on May 27, announced on-site temperature checks, respiratory and blood specimen collection, online questionnaires, access to telemedicine services, contract tracing and other services. Quest also said that because “some jobs are higher risk than others,” it will prioritize testing for organizations that employ healthcare workers, first responders and other companies that play a critical role in pandemic response.
https://www.biospace.com/article/labcorp-launches-covid-19-clinical-trial-connect/

Fauci: Moderna COVID-19 Phase III Trial to Begin in July with 30,000 Patients

Cambridge, Massachusetts-based Moderna is largely ahead of the game in the U.S. for developing a vaccine against COVID-19. On May 20, the company released positive interim Phase I data from its clinical trial of mRNA-1273. Yesterday, Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), which is collaborating on the vaccine with Moderna, told the editor of the technical journal JAMA that the vaccine’s Phase III trial is expected to launch in July. It will evaluate 30,000 patients ranging in age as 18 years and include the elderly.
Moderna’s vaccine uses unproven technology, mRNA. No therapy or vaccine has been approved based on the technology yet. Messenger RNA (mRNA) delivers the genetic code to the ribosomes where the protein is manufactured. In the Moderna vaccine, which is similar to a gene therapy, the mRNA codes for the virus’s Spike (S) protein. The patient’s cells then manufacture the S protein, which triggers the body’s immune system to recognize the virus itself.

The interim data released on May 20 was overall positive, although not without its critics, who believe the data was very early and incomplete. At that time the data was only two weeks old.
“That’s very early,” Anna Durbin, a vaccine researcher at Johns Hopkins University, told STAT. “We don’t know if those antibodies are durable.”
The Moderna press release also indicated that the antibody levels observed were equal to or greater in the 100 ug dose than was seen in patients who recovered from COVID-19. There’s not much context here, because studies on recovered COVID-19 patients have shown a range that is potentially influenced by the severity of the disease. For example, John “Jack” Rose, a Yale University vaccine researcher told STAT about a study in China demonstrating that in 175 recovered COVID-19 patients, 10 had no detectable neutralizing antibodies, while others had very high antibody levels.
Of the Phase III trial, Fauci indicated that the majority of trial participants will be between the ages of 18 and 55, but will include elderly Americans that are most at risk of serious illness from COVID-19.
“We are preparing the sites for the Phase III study,” he told Howard Bauchner, editor of JAMA. “The real business end of this all is the Phase III trial that starts in the first week in July.”
He also pointed out that NIAID, the federal government and Moderna and other companies developing vaccines against COVID-19 are scaling up manufacturing and producing vaccines in a gamble that the vaccines will be safe and effective.
“We are going to start manufacturing doses of the vaccines way before we even know the vaccine works,” Fauci said. “We may know whether it’s efficacious by November or December. By that time, we hopefully would have close to 100 million (doses).”
If the vaccine is safe and effective, they could have “a couple hundred million” doses available in early 2021. Of course, if it turns out to be a dud, they will have invested millions of dollars in a product that will have to be discarded.
Although Moderna’s vaccine is the leader in development, Fauci noted that several other companies, including AstraZeneca, which is working with the University of Oxford, are also developing potentially effective and safe vaccines. “There’s an array of at least four and possibly five trials that I am aware of and directly or indirectly involved in.”
President Trump’s Operation Warp Speed has a goal of manufacturing 100 million doses of a vaccine against COVID-19 by November, 200 million by December and 300 million by January 2021. This timeline doesn’t quite seem to match up with Fauci’s statements, and the timeline depends on everything going right, which is not a given. Operation Warp Speed has reduced a possible 93 vaccine programs to 14 top candidates, with expectations they will be further narrowed to six or eight.
Yesterday, Emergent BioSolutions, a contract development and manufacturing organization (CDMO), announced it had entered a public-private partnership under Operation Warp Speed worth about $628 million. Emergent will handle domestic production of leading COVID-19 vaccine candidates through 2021.
In a recent poll by the Washington Post-ABC News, 7 in 10 Americans indicated they would take a vaccine against COVID-19 if they were free and available to everyone. It had a political divide, however, with slightly more than 8 in 10 Democrats reporting they would definitely or probably get the vaccine, while slightly less than 6 in 10 Republicans said they would. Independents were somewhere in between.
About 15% of those polled said they would not get vaccinated, even if it is free and available to everyone. Among Republicans, that was claimed by 24%. Half of those said they do not trust vaccines in general and about a quarter of that group said a vaccine isn’t necessary in this case.
https://www.biospace.com/article/fauci-moderna-covid-19-trial-phase-iii-to-begin-in-july-with-30-000-patients/

Fitbit rises after its ventilator gains emergency use authorization

Fitbit (NYSE:FIT) gains 1.8% in after-hours trading after its Fitbit Flow emergency ventilator is granted Emergency Use Authorization by the U.S. Food & Drug Administration for use during the COVID-19 crisis.

Fitbit Flow builds on standard resuscitator bags, like those used by paramedics, with sophisticated instruments, sensors, and alarms that work together to support automated compressions and patient monitoring.

The company says it’s goal is to supply these devices to health care systems around the world that do not have a sufficient number of traditional commercial ventilators.

It’s in talks with state and federal agencies to understand current domestic needs for emergency ventilators and plans to work with U.S. and global aid organizations as well.

https://seekingalpha.com/news/3580229-fitbit-rises-1_8-after-ventilator-gains-emergency-use-authorization

Non-Warp Speed COVID-19 vaccine players under pressure

Certain COVID-19 vaccine developers that the Trump administration left out of the final round of Operation Warp Speed are under pressure on the loss of potential federal funding to support their development efforts.

Selected tickers: Vir Biotechnology (VIR -9.5%), Novavax (NVAX -13.6%), Dynavax (DVAX -4.4%), Altimmune (ALT -6.6%), BioNTech (BNTX -1.0%), Arcturus Therapeutics (ARCT -11.6%), Soligenix (SNGX), GeoVax Labs (OTCPK:GOVX -3.9%), Inovio Pharmaceuticals (INO -12.8%), iBio (IBIO -5.2%), Vaxart (VXRT -6.3%)

https://seekingalpha.com/news/3580197-non-warp-speed-covidminus-19-vaccine-players-under-pressure

Inovio hits speed bump in supply of COVID-19 vaccine candidate

Inovio Pharmaceuticals (NASDAQ:INO) has filed litigation in a Pennsylvania court against VGXI and GeneOne Life Science (together “VGXI”) aimed at forcing the latter to transfer its DNA plasmid technology to INO’s contract manufacturers so they can produce sufficient quantities of COVID-19 vaccine candidate INO-4800 for clinical trials and potential supply to the market, if approved.

Under a December 2019 agreement, VGXI as been the sole supplier of DNA plasmids to INO under “most favored” status although there are no purchase commitments and pricing is determined on per-order basis.

VGXI has informed INO that it lacks the capacity to make the volume of material in the requested timeline and it will be unable to make the plasmids for commercial sales of INO-4800. INO subsequently engaged third-party contract manufacturers to fill the void but they need VGXI’s technology to do so, a development that VGXI is balking over.

https://seekingalpha.com/news/3580228-inovio-hits-speed-bump-in-supply-of-covidminus-19-vaccine-candidate

Fed Will Expand Municipal Lending Facility to More Localities

The Federal Reserve said Wednesday it would again broaden the number of local governments from which it will buy debt through a forthcoming lending program.
The central bank said it would allow all 50 states to designate two cities or counties to sell debts directly to the central bank’s program, creating an option for states with less populous municipalities to participate.
The central bank also said governors of all 50 states will be able to designate an additional two issuers whose revenues are derived from operating activities, such as airports, toll facilities, utilities or public transit, to be eligible to use the facility on their own.
The Fed had previously made the program available to all 50 states, the District of Columbia, and one borrower for each county of at least 500,000 people and city of at least 250,000 — or as many as 261 issuers. Those thresholds had already been revised once, down from earlier cutoffs of 2 million and 1 million.
The changes will allow more than 100 new potential issuers to access the emergency lending program, which was first announced in April.
The Fed said it expects the program to lend up to $500 billion, and that volume hasn’t changed despite the two expansions of the program. The central bank has faced pressure from some elected officials to allow smaller cities and counties to access the program.

https://www.marketscreener.com/news/Fed-Will-Expand-Municipal-Lending-Facility-to-More-Localities–30717289/