*Update, 4 June 2018, 3 p.m.: While public health authorities and international organizations are trying to stop the Ebola outbreak in the Democratic Republic of the Congo (DRC), scientists have a rare chance to test new therapies on people infected with the virus, both to potentially help them and to gather data for the future. The DRC is considering testing several candidate Ebola drugs and antibodies that are in development. But the Ebola epidemic that exploded across West Africa several years ago showed that such trials are difficult to set up and conduct.
As the West African epidemic was winding down, Science took stock of each clinical study that researchers had conducted—or attempted to carry out—in the three most affected countries: Guinea, Liberia, and Sierra Leone. It was a thin harvest—except for a study of a vaccine produced by Merck, none of the trials yielded conclusive results. Some were able to enroll only a handful of patients, even though there were more than 28,000 cases; others suffered from not having a control group.
ScienceInsider is reposting that 31 December 2015 report below, as a background to the trials that are now under discussion during the DRC outbreak.
The DRC decided to use the Merck vaccine, which was shown to work in a large study in Guinea and is expected to be licensed by next year. Since 21 May, more than 1000 people have received it, and the study is expanding. An expert panel convened by the World Health Organization (WHO) said on 17 May that four unproven treatments merit being tested during the current outbreak under an “ethical framework” dubbed the Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI).
Two of those—an Ebola monoclonal antibody concoction called ZMapp and the antiviral drug favipiravir—were also tested in the West African outbreak. (Studies published in 2016 describe more detailed results from the trials of ZMapp and favipiravir.)
The two other treatments that passed MEURI muster are the antiviral drug GS-5734 and the monoclonal antibody cocktail REGN-EB3. The evidence for using these, the panel noted, was “well below the usual level evidence for formulating recommendations.” And a monoclonal antibody known as mAb114, the panel said, was too early in clinical development to meet MEURI standards. The WHO panel did not mention any of the other potential therapies tested earlier in West Africa—the antivirals brincidofovir and TKM-Ebola, the immune-modulator interferon, and the antibody-rich blood and plasma of survivors.
Whether scientists will learn more during this outbreak, which to date has identified 53 patients (25 of whom have died), will again depend on many variables. Most importantly, only the vaccine study has made it through the ethical and scientific approval process in the DRC, and the outbreak may well end before any of the trials get started. The antibody treatments can also require repeated infusions, and those aren’t feasible in the remote DRC locales where the bulk of the cases have surfaced.
Here is the original story from 31 December 2015:
Special report: Ebola's thin harvest
Since 29 November, not a single new Ebola case has been reported in Guinea, Sierra Leone, or Liberia. If no new cases pop up, the world will be able to declare on 14 January that the 2-year Ebola epidemic has ended at last, after more than 28,600 cases and 11,300 deaths.
Victory would also mean the end of an unprecedented era in Ebola research. The tragedy offered a unique opportunity: Never before had the disease affected enough people to allow researchers to test Ebola drugs and vaccines in a real-world setting. As the number of cases exploded in mid-2014, they set in motion a vast research program that operated at breakneck speed.
But the harvest of that massive effort is thin.
The biggest success so far is a vaccine produced by Merck. A 31 July report in The Lancet documented remarkable effectiveness in a real-world trial in Guinea. But all other results have yet to appear in the scientific literature. And a careful examination of the data so far—supported by dozens of interviews with the leaders of the studies and other Ebola experts—makes it clear that almost every other trial seems destined to end in questionable results or outright failure. Findings from those that have ended are proving difficult to publish in top-tier journals.
The reasons are varied and complicated. Even under the best circumstances, clinical trials don’t always deliver satisfying results. In this case, many studies started too late, when the epidemic was already declining, and ran out of patients. Others had designs that from the outset had little chance of providing a clear answer. A pharmaceutical company aborted a trial for reasons it never clarified, and the fate of another trial remains obscure even to the World Health Organization.
- TKM-Ebola: Negative results prove difficult to publish
A trial ends without an explanation
On 30 January, Chimerix of Durham, North Carolina, pulled the plug on a clinical trial of its experimental drug brincidofovir in Ebola patients. The drug, which mimics a DNA building block, is active against many viruses in test tube experiments and is in human studies to treat cytomegalovirus and adenovirus infections. But the Ebola test, started on 1 January by researchers working with Doctors Without Borders (MSF) at an Ebola clinic in Monrovia, was canceled after it had enrolled just four patients.
The announcement surprised even the scientists running the trial. “The press knew about it before I did,” says Stephen Kennedy, a Liberian investigator on the study. Lead researcher Peter Horby of the University of Oxford in the United Kingdom says Chimerix never told him the reasons either; in a press release the company simply noted that the number of new cases in Liberia had "decreased significantly."
Horby says he doubts the decision was related to how the drug performed in the first four patients. Instead, he believes Chimerix decided that it didn’t want to pursue bringing brincidofovir to market for Ebola after discussions with the U.S. Food and Drug Administration (FDA) raised questions about the interpretation of animal studies. FDA’s acting chief scientist, Luciana Borio in Silver Spring, Maryland, says she can't comment. “We’ve asked the company to disclose the facts surrounding the trial and we were not allowed to.” (FDA did not oversee the Liberian trial itself.)
"Someone should call Chimerix and ask them," says Marie-Paule Kieny of the World Health Organization in Geneva, Switzerland, who has coordinated the international research effort for Ebola. Science did that but a spokesperson for the company declined to comment.
Whatever the motivation, “it was frustrating," Horby says. “We invested a huge amount of resources, time, effort, in very difficult circumstances, as did MSF. It should not have been stopped unless it was for a very good reason.” With so few patients enrolled, results from the study are "uninterpretable," says Horby, who nonetheless still hopes to publish a paper about it.
Negative results prove difficult to publish
At the peak of the Ebola epidemic in September 2014, the World Health Organization (WHO) gathered experts in Geneva, Switzerland, to review the myriad potential treatments and help identify the most promising ones. The panel gave top priority to interventions that had been shown to work in monkeys experimentally infected with Ebola—and a drug named TKM-Ebola ended up at the front of the pack. Made by Tekmira Pharmaceuticals Corporation of Vancouver, Canada, TKM-Ebola interferes with the Ebola virus RNA.
But the company had precious few doses, and a formal clinical trial was slow to start. Some researchers also frowned because the study, launched on 11 March in Sierra Leone, did not have a randomized-controlled design. But Peter Horby, a respected researcher from the University of Oxford in the United Kingdom, headed the study, and the Wellcome Trust funded it. Hopes ran high that it would at the very least give a hint whether the encouraging monkey results would be borne out in humans.
On 19 June, however, Tekmira suddenly ended the study, without fully explaining why. Horby says after testing the drug on 14 patients, the study had reached a predefined "futility boundary." That means enrolling further patients was "unlikely to show that the drug was significantly beneficial," he says.
The lack of a clear benefit was "a bit of a disappointment," Horby says, but he notes that it's not uncommon for drugs to work in monkeys and then fail in humans. One problem may have been that the animals were treated early in their illness; most Ebola patients seek care very late, he says.
Horby's next disappointment came when The New England Journal of Medicine (NEJM) rejected a paper describing the results. He speculates that scientific publications are losing interest in Ebola, and the fact that this study lacked a randomized design and clear outcomes worked against it as well.
“The journals have published large amounts of anecdotal data on one or two cases and hundreds and hundreds of opinion and commentary pieces, but we're struggling to publish informative but not definitive data from trials,” Horby says. Although he understands that negative studies are less exciting, "you have to balance that against the enormous difficulty of doing these trials and the almost complete absence of any data on treatment effects."
WHO Assistant Director-General Marie-Paule Kieny shares his frustration. "It's problematic because it's very important that these results are out in the open," she says. A spokesperson for NEJM says she cannot comment because the journal's publication process is confidential. Horby says the paper is now under consideration at another journal.
A big study fails to give solid answers
The largest treatment study done in the Ebola epidemic tested favipiravir, an influenza drug. The trial has ended after enrolling more than 200 people, and its results may soon appear in a scientific journal. But the study can't give a clear answer to the key question: Does it work?
Favipiravir, which inhibits a critical viral enzyme called RNA polymerase and is being developed by Fujifilm in Japan, showed anti-Ebola activity in test tubes and in mice. Early in the outbreak, it had a great advantage over other drug candidates: It was plentiful and had proved safe when given to healthy volunteers in phase I trials. Researchers at France's National Institute for Health and Medical Research (INSERM) started a collaboration with researchers in Guinea, a French-speaking country, to test favipiravir at four Ebola treatment units.
In February, the INSERM researchers presented what they said were encouraging preliminary results based on the first 69 patients. The drug seemed to save lives of people who came to clinics with low levels of the Ebola virus, they said. French President François Hollande hailed the results in a press statement and invited Ebola research leaders to the Élysée palace in Paris. Since then, all Ebola patients in Guinea have been offered favipiravir.
Many researchers were less impressed. The INSERM team didn't use a randomized controlled trial (RCT) design but gave all eligible patients the drug; their outcomes were compared to a group of Ebola patients who fell ill before the trial started. The problem is that mortality depends greatly on the quality of Ebola care, which varied widely over time and from one treatment center to the next. That made such comparisons tricky. The drug also only worked in people who, without treatment, had a much better chance of surviving Ebola because when they first sought care, they had relatively low levels of virus in their blood.
An RCT would have been impossible, says INSERM researcher Denis Malvy; it was unacceptable to the local population, already very distrustful of its government and foreign Ebola workers. He says building research collaborations was difficult enough without the added stress of asking local collaborators to withhold treatment to a control group. "It's easy to criticize a study," he says. "We set out to look for a signal, not formal proof of efficacy."
Yet now, nobody is sure whether favipiravir should be used in the next Ebola outbreak. That’s the bottom line, says Luciana Borio of the U.S. Food and Drug Administration, and it shows that uncontrolled studies can cause more harm than good. “It resulted in that nebulous data zone that we were so fearful about,” Borio says. “We’re left with not knowing whether the product helps, hurts, or does nothing.”
The study design was also one of the reasons the New England Journal of Medicine (NEJM) rejected a paper about the results, Malvy says; instead the journal offered him a 300-word letter to the editor, which he says was laughable. (An NEJM spokesperson declined to comment.) The study is now under review at PLOS Medicine, Malvy says.
A trial that that few believed in
When Ebola spiraled out of control in the summer of 2014, immunologist Eleanor Fish of the University of Toronto in Canada thought she had something that might save lives. Because no treatments were available, Fish said it made sense to try interferons, a group of biochemicals with antiviral activity that she had long studied.
Many Ebola scientists disagreed.
Fish sent the World Health Organization (WHO) a study showing that interferon-α, delivered by an adenovirus and combined with an antibody cocktail, had efficacy in monkeys infected with Ebola. But other researchers noted that interferons alone had not been shown to do anything. A panel asked by WHO to prioritize drugs for testing considered interferons "problematic.” Side effects such as fever and muscle pain—which are similar to Ebola symptoms—could create problems in Ebola treatment centers, the group said. "Basically, all of the interferons don't work," Peter Jahrling, a veteran Ebola researcher at the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, said at a WHO meeting, summing up the animal evidence for Ebola therapies. "I don't know why you'd want to do a clinical trial with them."
Given the lack of alternatives at the time, Fish pushed ahead with a test of interferon-β, which in vitro studies suggested was the form most effective at thwarting Ebola’s replication, she says. She teamed up with Guinean epidemiologist Mandy Kader Kondé to set up a clinical trial in the Ebola treatment center in Coyah, some 2 hours northeast of the capital, Conakry. But it took until March 2015 to write the protocol and get the study approved by Guinean regulators. By then the number of Ebola cases had dropped sharply. Because interferons may make matters worse if taken late in the infection, the trial only enrolled patients within 6 days after the onset of symptoms, which further limited enrollment.
In the end, only nine patients took part in the study. All received interferon-β; having a placebo arm was unacceptable in Guinea, Fish says, so the patients' outcomes were compared with those of 21 untreated patients, matched for age, who were seen at the same center in the same period. Given the study’s design and small size, “I don’t think there will be anything coming out of that,” says WHO’s Marie-Paule Kieny.
But Fish disagrees. “Statistical analyses indicate that [interferon] offered a therapeutic advantage,” she wrote in an email to Science. “We have a number of measures that we evaluated that support this.” Fish declined to elaborate but said the data will soon be submitted for publication.
A front-runner fades
ZMapp, a cocktail of three artificial Ebola antibodies, has been the darling of the research world and the media since missionaries Kent Brantly and Nancy Writebol received the treatment in the summer of 2014. CNN described it as a “secret serum that likely saved" their lives. CNN reporter Sanjay Gupta—a medical doctor—said a source described how Brantly had a “sudden deterioration” in Liberia and “thought he was going to die,” but after receiving ZMapp, “within 20 minutes to an hour” he had “a near complete reversal of his symptoms.” Yet going from individual cases to statistical evidence that the drug really works in people has proven difficult.
ZMapp had worked brilliantly in monkey experiments, even rescuing animals at an advanced stage of infection. When the antibody cocktail was given to animals up to 5 days after they were infected with the Ebola virus, all of them survived, scientists reported in Nature in August 2014. Veteran Ebola researcher Thomas Geisbert of the University of Texas Medical Branch in Galveston called the result a “monumental achievement.” But ZMapp, made by Mapp Biopharmaceutical in San Diego, California, was in such short supply that by mid-February 2015, only nine people had received it—and a few had died, underscoring that whatever its potential, it had limitations.
It took until 27 February for a formal randomized controlled trial of ZMapp to begin in Liberia, spearheaded by the U.S. National Institute of Allergy and Infectious Diseases (NIAID). But by then, the epidemic in Liberia was practically over. The team expanded the study to Sierra Leone and struck up a collaboration with French researchers working in Guinea to recruit patients there. (One patient in the United States was also enrolled in the trial.)
But time wasn't on the study’s side. To date, the trial has only enrolled about 70 patients, says NIAID's lead researcher Clifford Lane in Bethesda, Maryland. Complicating the study is the fact that patients in Guinea also receive favipiravir, based on an inconclusive French study in that country that suggested it had an anti-Ebola effect. The ZMapp team will do a subset analysis by country to see whether the effects of the two drugs can be disentangled.
Whether the erstwhile front-runner will be shown to work remains the big question. The study has an independent Data Safety and Monitoring Board (DSMB) that looks at the outcomes once every month or so. “They haven’t stopped the trial yet, so we know that it must at least do something,” says the World Health Organization’s Marie-Paule Kieny, who is still hopeful that ZMapp will become the Ebola epidemic’s second clinical success story, after Merck’s vaccine.
But Lane is more cautious. “It is very difficult to read between the lines of a DSMB recommendation,” he says. Nevertheless, “I’m hopeful that even if the data don’t reach statistical significance, there might be at least a trend for efficacy from humans that support the animal data.”
A trial whose fate is unclear
People who survive an infection like Ebola have a powerful weapon in their blood: antibodies that have conquered the invading microbe. In principle, an infusion of survivors’ blood could be a lifesaver for newly infected people. But an early study in Sierra Leone testing that concept has remained unpublished—and nobody seems to know what happened with the data.
The World Health Organization (WHO) pushed for studies of blood-based therapies early in the Ebola epidemic because the most promising drug candidates were in short supply, while the number of survivors was growing. The studies can be done with either whole blood or its plasma, which has the cells removed; the latter is far more technically challenging, because it requires so-called plasmapheresis machines to separate plasma and cells.
Sahr Gevao, a hematologist at the University of Sierra Leone in Freetown and a consultant to the country's Ministry of Health and Sanitation, decided to try the simpler option early on. A study of whole-blood transfusion started in the fall of 2014 at the 34 Military Hospital in Freetown. But around the same time, an international consensus emerged that using plasma was the way to go, and collaborations were set up to ship plasmapharesis machines to West Africa and test that strategy in all three Ebola-affected countries.
The whole-blood study in Sierra Leone appears to have ended in late 2014; Gevao went on to become the principal investigator of the country's plasma study, carried out in collaboration with the University of Liverpool in the United Kingdom and other partners.
But data from the whole-blood study never got published. A few news reports suggested that it was successful, and Wiltshire Johnson of Sierra Leone's Pharmacy Board, charged with overseeing clinical trials in the country, told Science that 33 out of 44 patients who received a transfusion survived. Those are much higher survival rates than were being reported at the time for untreated Ebola. But scientists caution that it's unclear how patients were selected for the trial, or whether their care differed in other ways that made them more likely to survive.
Gevao didn't respond to emails from Science. Scientists working on the plasma studies say they don't know what happened with the whole blood study. Neither does WHO. "I haven't seen the results yet," says WHO Assistant Director-General Marie-Paule Kieny. "We need to chase that; we need to know what happened."
Cloudy results from filtered blood
The blood of Ebola survivors contains antibodies that could help people sick with the disease, but blood is a precious commodity: Donors can’t be bled often, and the product must be used within a few months. An attractive alternative is plasma, which contains the same antibodies but has the red blood cells separated out and given back to the donor. People can donate plasma every 2 weeks instead of every 3 months, and frozen plasma lasts a year or more. Plasma infusions also take less time, an important consideration in an Ebola treatment center. But this promise hasn't panned out in the epidemic.
Thanks to the Bill & Melinda Gates Foundation and other donors, expensive plasmapheresis machines to separate plasma from blood were sent to all three Ebola-affected countries for use in clinical studies. But two of the three trials never really got off the ground. A study in Liberia kicked off in December, and researchers had enrolled only six patients before that country's epidemic came to an end. It took until March in Sierra Leone to start a plasma study, and only three patients entered.
The one study that managed to recruit a large number of patients took place at a Doctors Without Borders treatment center in Conakry, the Guinean capital. Run by scientists from the Institute of Tropical Medicine in Antwerp, Belgium, and Guinea's National Blood Transfusion Center, the trial enrolled 102 patients even as the epidemic was winding down. In September, the researchers reported in Clinical Infectious Diseases that the treatment is safe, acceptable, and feasible even in the midst of an outbreak. That's quite a feat in itself, says first author Johan van Griensven, who declined to discuss the outcomes; a paper describing the results will come out on 7 January 2016 in a top scientific journal, he says.
But the results will be difficult to interpret—not because of a lack of patients but because of the design. The researchers initially thought that because plasma of the right blood type would not be available for some people early in the study, a control group of untreated patients would form naturally. That didn't happen—plasma soon was plentiful, whereas patients were scarce—so instead the team compared the 2-week survival rate of plasma recipients with that of patients in the months before the study started.
That's a difficult comparison, however, because the treatment center was flooded with patients in the months preceding the trial, which may have resulted in lower quality care and a lower survival rate. So even if the data show that plasma recipients were more likely to survive, that may be because they got better care.
The only real success story so far
On 26 September 2014, the U.S. Centers for Disease Control and Prevention (CDC) released a projection that shocked the world. Based on its epidemiologic models, CDC estimated that if the lackluster response to the Ebola epidemic continued unchanged, Sierra Leone and Liberia alone could have up to 1.4 million cases by January. A vaccine seemed the only hope to avert this catastrophe.
GlaxoSmithKline (GSK) and Merck raced forward with tests of two vaccines in the affected countries. Each has the Ebola virus surface protein gene stitched into a harmless viral “vector”: GSK uses a chimpanzee adenovirus, whereas Merck relies on a livestock pathogen called vesicular stomatitis virus (VSV). But by February 2015, when the first large-scale vaccine trials began, the model had been proven misleading: The epidemic was petering out because of ramped-up containment efforts. Cases became so rare in Liberia that it had to downgrade a phase III trial of both vaccines to phase II after enrolling a mere 1500 of an anticipated 27,000 participants.
As a result, there is no verdict on the efficacy of the GSK vaccine. But the VSV vaccine had another shot at proving its worth. In a move that yielded the only solid success of any Ebola trial, an international consortium led by the World Health Organization launched a test of the Merck vaccine in Guinea with a novel design, which gleaned results even as cases dwindled. Instead of the traditional vaccine trial that randomly assigns people to receive a shot or a placebo, this study used a design called ring vaccination, following the epidemic where it went. It targeted clusters of people who had been in contact with a confirmed case, as well as the contact’s contacts, and compared them with similar clusters that did not receive the shots until 3 weeks later.
On 31 July, the researchers announced that the trial was a stunning success: No one who received the vaccine developed the disease 10 days or more after the shot—presumably the length of time it takes to develop immunity. In the clusters that had to wait for the vaccine, 16 people contracted Ebola.
The unusual trial design yielded data that were not deemed strong enough to lead regulatory bodies to license the vaccine, but they went a long way toward convincing the world that an Ebola vaccine is at hand—and that it might have the power to prevent future outbreaks from ever becoming this big again.
*The Ebola Files: Science and Science Translational Medicine have made a collection of research and news articles on the Ebola virus and the recent epidemic freely available to researchers and the general public.
*Update, 3 January, 4:00 p.m.: A trial of the Merck and GSK vaccines in Liberia wasn't abandoned, as this story previously said, but converted from a phase III to a phase II study. It continues to gather safety and immune response data.