Master protocols emerge as a critical clinical tool against COVID-19
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Master protocols are finally moving center stage, offering the fastest path to definitive answers on what will be the safest and most effective treatments for COVID-19. If master protocols prove their value in this disease, it may lower the activation energy for the trial designs to take hold in standard drug development after the crisis is over.
At least five master protocols are under way to test repurposed agents; the next step is to apply the structure to novel therapies.
These large-scale trials simultaneously evaluate multiple treatments or patient populations under a single study protocol and set of endpoints.
The benefits are efficiency, which comes from the parallel testing and sharing of a control arm, and generation of data that can be meaningfully compared across treatments (see figure “Master protocol subtypes”).
Figure: Master protocol subtypes
At least three types of trials fall into the category of master protocols: adaptive trials, basket trials and umbrella trials.
For COVID-19 therapies, the focus is on adaptive trials, which evaluate multiple treatments in a single population with a single standard of care control arm. At interim analysis points, treatment arms can be added or dropped, and the trial can be designed to continue with different treatment arms indefinitely.
Basket trials are the opposite, and evaluate a single treatment across multiple patient populations. These trials have been used in cancer, where a single therapy may benefit patients with different tumor types. Basket trials often lack a control. When they are placebo controlled, there is a control group for each patient population.
Umbrella trials stratify patients based on genetic sequences, and treat each subgroup with different treatments. Each arm is individually randomized with control. This trial type has also been used to evaluate cancer therapies.
For the first wave of COVID-19 therapies, there’s little question that master protocols are the best route, as they can provide critical information to regulators and physicians trying to make sense of the mess of data pouring in from small, non-controlled studies.
This week, a coalition of regulators including EMA highlighted concerns that small trials and compassionate use programs are unlikely to generate the evidence needed to draw conclusions on clinical efficacy, and called for robust coordinated trials such as master protocols to generate data for COVID-19 therapies (see “Coalition of Regulators Call Coordinated Trials Key”).
“When you have a new disease like this, everyone is eager to share information as quickly as possible, and that means we see a lot of very small groups suggest treatments are effective or ineffective based on a small number of patients and a non-standardized way of treating,” said Justin Denholm, associate professor at the University of Melbourne.
“The trials are potentially suggestive at best, but at worst, they drive inappropriate prescribing patterns that lead people to either abandon useful treatments too quickly or rush to encourage use of medications without demonstrated efficacy and unacceptable side effects,” he added.
Chloroquine and hydroxychloroquine, the only drugs so far to receive emergency use authorization (EUA) in the U.S., were authorized on limited in vitro and anecdotal clinical data. The authorization raised concerns about deterring patients from trials of therapies that could be more effective and about toxicities, highlighting the urgent need for the kind of systematic analysis of controlled data that master protocols produce (see “Despite Lack of Controlled Data, FDA Authorized Hydroxychloroquine and Chloroquine”).
“I think this crisis will highlight how important these trials are for infectious diseases. I’ve called for that for many years.”
While the duplication has a greater spotlight now because of the urgency in COVID-19, it’s a problem the industry has borne for years. A few master protocols have been set up for cancer, but the structure hasn’t been widely adopted by companies accustomed to running and controlling individual trials (“Back to School: Haste not Waste”).
“I think this crisis will highlight how important these trials are for infectious diseases. I’ve called for that for many years,” Luciana Borio, VP at In-Q-Tel Inc. and former FDA acting chief scientist, told BioCentury.
“If we could establish common protocols across the United States or even globally, we could accelerate knowledge, and gain knowledge for things that are traditionally very difficult to study. We create efficiencies by using a shared control arm, and by not stopping studies and starting them from scratch. There are so many reasons to do standard protocols.”
Protocols to repurpose
The five master protocol trials under way for COVID-19 employ adaptive trial designs, meaning agents can be added and dropped at interim analyses. Four of these trials are starting by testing generic drugs (see “COVID-19 Master Protocol Trials”).
The fifth, NIH’s ACTT (Adaptive COVID-19 Treatment Trial), is evaluating the investigational antiviral remdesivir from Gilead Science Inc. (NASDAQ:GILD). On Friday, Eli Lilly and Co. announced the study would add an arm to treat patients with Olumiant baricitinib, a JAK1/JAK2 inhibitor approved to treat rheumatoid arthritis (RA).
Table: COVID-19 master protocol trials
At least five master protocol trials evaluating generic drugs or novel therapies to treat COVID-19 have been disclosed.
The U.K. RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial, the WHO’s SOLIDARITY trial, the international REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) study and the Australian ASCOT trial are focused initially on repurposed generic drugs, although several could expand into novel therapies as they become available.
The NIH’s Adaptive COVID-19 Treatment Trial (ACTT) is focused on investigational treatments.
The table includes trials of COVID-19 therapeutics. There is also at least one master protocol for COVID-19 vaccines.
Sources: Company and institution websites, ClinicalTrials.gov
The adaptive trials depend on Bayesian statistics to quickly determine which treatments are working based on limited data. With an early signal that a compound is doing well, the trial can be adapted to add more patients to that treatment arm, or even make that treatment the standard of care against which other treatments are evaluated. The better a drug is working, the faster the data supporting it will be generated.
The WHO’s SOLIDARITY study is gaining status as the template to follow, providing a road map upon which other trials for repurposed drugs are modeled.
The trial, initially set up to evaluate four different treatments for COVID-19, plans to compile data from sites in at least 70 countries. All of those sites will use the same inclusion criteria, randomization protocols, endpoints and statistical methods for data evaluation, although each may select which treatment arms to include from the main protocol.
Denholm, who is a principal investigator on the ASCOT master protocol trial about to kick off in Australia and New Zealand, told BioCentury the ASCOT trial’s structure is closely aligned with SOLIDARITY to allow data sharing. But ASCOT’s sponsors decided to create a separate trial rather than run an Australian arm of SOLIDARITY in order to evaluate a different primary endpoint.
As of this week, there are no SOLIDARITY trial arms in Australia.
“We’re capturing the same data points they’re looking for in SOLIDARITY so that as we go, we’ll have the capacity to combine outcomes with theirs, but we wanted the main outcome of our trial to be something quickly and easily assessed without subjectivity,” said Denholm.
He said that by aligning the different master protocol trials and collecting similar databases, it may be possible to gather data that wouldn’t be available from any individual trial.
"We see a lot of very small groups suggest treatments are effective or ineffective based on a small number of patients."
“There are questions that no one is going to power a major master protocol trial to answer, such as whether certain anti-hypertension drugs might be associated with better or worse outcomes on a certain COVID treatment. If we can look across databases from around the world, that might give us the power to look back and see where the strong signals are,” said Denholm.
Denholm noted that SOLIDARITY uses a point-based scale to measure disease severity at the end of the evaluation period, which introduces some subjectivity and possible inter-site variability. ASCOT will collect that data as a secondary endpoint, but the primary outcome is “about death and ICU-level care.”
Two other trials, the U.K.’s RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial and the international REMAP-CAP (Randomized, Embedded Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) trial, are also using more objective primary endpoints.
The RECOVERY study will measure in-hospital mortality, and the REMAP-CAP trial, which has been expanded from its original community-acquired pneumonia and influenza patient base to include COVID-19 cases, is using days alive and outside the ICU as a new endpoint during the pandemic.
University of Oxford professor Richard Haynes said the RECOVERY trial is working with EMA and different stakeholders including the WHO to “coordinate rather than duplicate effort.” Investigators from the REMAP-CAP trial did not respond to requests for comment.
All four of the trials have treatment arms for hydroxychloroquine and the lopinavir/ritonavir combination, but vary in the other drugs they are testing.
ASCOT is randomizing patients to receive hydroxychloroquine, lopinavir/ritonavir, both treatments or SOC. The other trials are evaluating those two drugs plus others, including interferon-β, remdesivir and Kineret anakinra from Amgen Inc. (NASDAQ:AMGN), a recombinant form of IL-1RA.
According to Denholm, the ASCOT team is continuously monitoring in vitro screens for drugs with activity against COVID-19 and clinical trial data for any early signals to determine which new drugs to add to the protocol.
None of the trials has disclosed when data will be available.
Adapting to new therapies
Investigational new therapies aren’t seeing the same rush into master protocols because most haven’t yet hit the key criteria for inclusion. But companies developing novel COVID-19 agents still stand to benefit from the trial design.
While master protocol trials take away some level of control over how the trial is run, they offer a low-cost avenue to determine whether a therapy is working, or maybe more importantly not working, based on a small data set.
They can also more rapidly demonstrate to physicians and regulators how individual therapies stand up to the flood of other new candidates moving through the clinic.
To date, NIH’s ACTT trial is the only master protocol designed with a focus on investigational new therapies for COVID-19 from the outset, but the other trials may be adapted to assess newer treatments once they yield enough data on the repurposed drugs.
The trial’s first arm is Gilead’s remdesivir because the molecule is the most advanced candidate.
“Early on, it’s possible that a trial like this would evaluate just one experimental therapy, but as more become available, the study can add arms and share a common control arm, which adds to the efficiencies,” said Borio.
“mAbs are super promising, but they won’t be available for clinical studies until manufacturing capacity reaches a certain threshold.”
Olumiant is now the second drug added to the protocol. Although it’s on the market for RA, it was approved in 2018 and is still on patent. It hasn’t been tested in other master protocol trials.
Some of the next candidates might be the cocktails of mAbs. “Monoclonal antibodies are super promising, but they won’t be available for clinical studies until manufacturing capacity reaches a certain threshold. That may be May, June or July. The timing of availability might factor into the sequences of the different investigational agents,” said Borio.
Although Borio is not involved in the ACTT trial, she led the FDA team involved in the 2014 iteration of the master protocol for Ebola.
The ACTT trial, which started enrolling for the remdesivir and placebo arms in late February, has passed its target enrollment of 400 patients but will continue enrolling.
In a press release issued on Friday, Lilly said data for the Olumiant arm would be available in about two months.
The SOLIDARITY trial also has a remdesivir treatment arm. Haynes told BioCentury the RECOVERY trial may add novel therapies in the future.
Denholm said that repurposed drugs are the priority because they have already established their safety in other patient populations. “Using novel treatments means we need to build up more slowly to watch for safety issues, look across a much broader range of safety signals, and look for them more frequently,” said Denholm.
Most investigational new therapies for COVID-19 also haven’t reached sufficient manufacturing capacity for the trial design, which can involve a rapid scale up.
But having the master protocol trials up and running means new compounds can be added as they become available, streamlining the time-consuming administrative steps required get a trial off the ground.
Convalescent serum may also benefit from an overarching master protocol.
FDA and other government agencies are using a centralized protocol to facilitate access to convalescent plasma, and to provide a clear read on whether plasma from a recovered patient can help treat the infection in others (see “Collaboration, Standardization Will Bring Access to Convalescent Plasma”).
For vaccines, a master protocol has the potential to speed up data generation by months, according to the WHO. The organization’s plan for a master protocol trial evaluating multiple vaccines in parallel suggests concurrent evaluation of benefits and risks may be possible within three to six months of the vaccine being made available for the trial (see “WHO outlines first master protocol for COVID-19 vaccines”).
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IL-1RA - Interleukin-1 receptor antagonist