NIAID-Backed Hyperimmune Intravenous Immunoglobulin Fails to Meet Endpoints: TrialSite Reminder of the Lessons of Plasma Politics & Power

NIAID-Backed Hyperimmune Intravenous Immunoglobulin Fails to Meet Endpoints TrialSite Reminder of the Lessons of Plasma Politics & Power

Another National Institute of Allergy and Infectious Diseases (NIAID)-backed large scale COVID-19 experiment failed to meet endpoints as the CoVIg-19 Plasma Alliance recently shared that the Phase 3 Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) results disappointed. NIAID, part of the National Institutes of Health (NIH), helped fund with taxpayer dollars the investigation into whether anti-coronavirus hyperimmune intravenous immunoglobulin (H-Ig) medicine or “CoVIg-19” could reduce the risk of COVID-19 disease progression when combined with standard of care treatment, including remdesivir in hospitalized adult patients at risk for serious complications. Previously reported on by TrialSite while the analysis remain ongoing, and the federally-financed research institute and its INSIGHT Network still desire to publish the results. They reported no serious safety signals and Bill Mezzanotte, MD, MPH, Executive Vice President, Head of Research and Development and Chief Medical Officer of CSL Behring and co-leader of the CoVIg-19 alliance, quoted that the results of this clinical trial were “disappointing.” However, the team was proud of contributions, including “a growing understanding of this challenging virus and strategies for patient care.” While H-Ig medicine is an experimental regimen derived from the liquid portion of the blood (plasma) donated by healthy people who recovered from COVID-19 and then highly purified, TrialSite reminds all of the plasma turf wars that became apparent in August 2020 between on the one hand the NIH/NIAID and their initiatives ceded to the public-private ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) and on the other hand the investigator-initiated “Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID-19,” a non-randomized controlled study led by Dr. Michael Joyner of the Mayo Clinic: all essentially investigating the same convalescent plasma question. Tensions and an internal clash led to the U.S. Food and Drug Administration (FDA) issuing an emergency use authorization (EUA) for convalescent plasma despite the behind the scenes moves by NIH Director Francis Collins and NIAID Director Anthony Fauci to counter such a move. 

CoVIg-19 Plasma Alliance

The CoVIg-19 Plasma Alliance was the result of a number of players coming together to help fight against the COVID-19 pandemic; the group developed a potential plasma-derived therapy for people at risk for serious complications from COVID-19. Bringing together the world’s leading plasma companies to work on the development of an investigational unbranded polyclonal anti-SARS-CoV-2 hyperimmune globulin medicine intended for the treatment of patients at risk for serious complications from COVID-19, the group developed what they positioned as a “high-quality pharmaceutical product” made of purified and concentrated levels of convalescent antibodies.

This alliance was co-founded by private sector players (CSL Behring and Takeda) and included other players, both private sector, nonprofit and supported by the government. This Alliance included BioPharma Plasma, Biotest, GC Pharma, LFB, National Bioproducts Institute, Octapharma and Sanquin. The Bill & Melinda Gates Foundation provided advisory support. Microsoft provided technology, including the Alliance website and the Plasma Bot for donor recruitment. Organizations including Pall and Uber Health also made in-kind contributions.

A Major Blood Drive

This effort was part of “The Fight Is In Us” campaign which is a coalition seeking to mobilize tens of thousands of people in the United States who have recovered from COVID-19 to donate their blood plasma.

The Study

The ITAC trial (NCT04546581) is a Phase 3 global, multi-center, double-blind, placebo-controlled, randomized trials sponsored and funded by the NIAID.  This study was designed to test the safety, tolerability and efficacy of the combination treatment regimen consisting of standard of care including remdesivir with an anti-coronavirus hyperimmune intravenous immunoglobulin (H-Ig), which contains a highly concentrated solution of antibodies that neutralize SARS-CoV-2. The antibodies in the H-Ig come from the liquid portion of blood, or plasma, donated by healthy people who have recovered from COVID-19.

Through the NIAID-funded INSIGHT Network, the study team enrolled nearly 600 adult patients at 63 sites in the United States and 10 other countries on five continents. Volunteers were eligible for the trial if they had been hospitalized for COVID-19 and had symptoms for 12 days or fewer without life-threatening organ dysfunction or end-organ failure. Four companies provided investigational H-Ig materials for the trial, including CSL Behring and Takeda on behalf of the CoVIg-19 Plasma Alliance, as well as Emergent BioSolutions and Grifols.

Plasma, Politics & Power Struggles

The FDA issued an emergency use authorization (EUA) for the use of convalescent plasma despite the NIH’s position that more data was needed. In February 2021, the FDA updated the FDA issued a revision to its EUA for COVID-19 “as a result of our evaluation of the most recent information available.”

The FDA had made a move that was considered by many experts that TrialSite had spoken with as a politically-inspired move, probably influenced by the previous White House to drive some positive activity. A reminder of what gave the public a glimpse into the political squabbles involving politicians, regulators and NIH institute bureaucrats were articles back in August 2020. In August 2020, TrialSite first reported on the FDA’s decision to halt the use of convalescent plasma for COVID-19—that was the Mayo Clinic-led protocol first commenced during the first tragic wave of the pandemic in the Spring of 2020. TrialSite found that Mayo Clinic investigators were “puzzled” by the decision and there was evidence that NIH’s Director Dr. Francis Collins and NIAID Director Dr. Anthony Fauci intervened with the FDA to at least temporarily halt a plasma EUA.

One challenge could have been competition for patients (and general turf over who controls research) as the NIH wanted to run many ongoing experiments via its Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) associated with plasma, including the study (ITAC) reported on today.  

In fact, while Joyner was getting close to reporting their expanded use findings, the NIH launched what in essence was a competing convalescent plasma trial with NIAID’s INSIGHT Network (International Network of Strategic Initiatives in Global HIV Trials).

Dr. Michael Joyner of the Mayo Clinic led the investigator-initiated and organized National Convalescent Plasma initiative along with 34 other institutions from 17 states in a non-NIH orchestrated, nationwide trail site network.  

This project included 8,000 doctors, 3,000 hospitals and 100,000 enrollees. While there were rumblings that this national protocol study (not a formal randomized controlled trial) was “monopolizing patients,” Dr. Joyner declared, “That’s a false dichotomy.”

In August, the findings from Joyner’s initiative were somewhat positive on the one hand, but due to a confluence of factors, the study results didn’t lead to powerful evidence confidently advancing practice—yet it was this very initiative that led to the FDA’s authorization under emergency use.

During this time, more than likely due to pressure from the White House, the FDA was about to issue an EUA for plasma but Collins and Fauci intervened, positing that the data on efficacy was inadequate. Results so far from the Mayo project were considered by the research bureaucrats as unreliable as there was no control group—no randomized controlled trial.  

Back then, CNN reported that the then POTUS announced the FDA will maintain an EUA for convalescent plasma. Some kind of political jostling was obvious and apparent to all, right in the middle of the worst pandemic in modern history! TrialSite reported, “Trump vs Fauci: Emergency Use Authorization Issued for Convalescent Plasma for COVID-19” to evidence this flurry of activity prior to the final EUA issuance for convalescent plasma.

At least for now, the EUA stands despite the most recent data in the ITAC trial, which of course is just one of a number of studies involving some form of convalescent plasma.

A Large NIH-backed Convalescent Plasma Study Halted

Just in the beginning of March 2021, the National Heart, Lung and Blood Institute (NHLBI), part of the NIH, halted yet another convalescent plasma clinical trial evaluating the safety and effectiveness in the emergency department settings for those individuals who had developed mild to moderate COVID-19 symptoms. The independent data and safety monitoring board (DSMB) met on Feb 25, 2021 determined that while the investigational treatment caused no harm, it was unlikely to benefit this group of patients. Known as the C3PO study, TrialSite reported that the NIH and its institutes continued to back large, high cost studies in the midst of the pandemic with an investigational product that many doctors and experts had already concluded wasn’t the right direction.  

Why Continue Convalescent Plasma Studies?

While at this time monoclonal antibodies were already authorized under EUA and could have been administered to these patients potentially, we suggested the NIH start putting real investment into generic or low cost repurposed drug trials (ivermectin, fluvoxamine, colchicine, etc.) for early-onset care options for mild to moderate COVID-19 cases, which represent the overwhelming majority of COVID-19 cases.