Study Leaders Publish Results from NIH-DRC-WHO Clinical Trial of Four Experimental Therapies
November 27, 2019
The Ebola treatment center (ETC) in Beni, Democratic Republic of the Congo. Operated by The Alliance for International Medical Action (ALIMA), the Beni ETC enrolled patients in the PALM study of Ebola therapeutics. The ETC is now operated by MSF.
The investigational therapeutics mAb114 and REGN-EB3 offer patients a greater chance of surviving Ebola virus disease (EVD) compared to the investigational treatment ZMapp, according to published results from a clinical trial conducted in the Democratic Republic of the Congo (DRC). The new report also shows that early diagnosis and treatment are associated with an increased likelihood of survival from EVD.
The results appear online this week in The New England Journal of Medicine. An announcement made on August 12, 2019, noted that the study leaders halted the trial early, on August 9, 2019, as recommended by an independent data and safety monitoring board based on its review of preliminary data from 499 study patients. The preliminary analysis found that both mAb114 and REGN-EB3 performed better than ZMapp. The fourth drug, remdesivir, performed similarly to ZMapp. Today’s publication provides a comprehensive analysis of the full dataset from nearly 200 additional patients enrolled in the clinical study.
The clinical trial known as PALM, short for “Pamoja Tulinde Maisha,” a Kiswahili phrase that translates to “together save lives,” was organized by an international research consortium coordinated by the World Health Organization (WHO). It is led and funded by the DRC’s National Institute for Biomedical Research (INRB) and Ministry of Health, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health. Professor Jean-Jacques Muyembe-Tamfum, M.D., Ph.D., director-general of the INRB and head of the DRC’s Ebola response, and Richard T. Davey, Jr., M.D., deputy director of NIAID’s Division of Clinical Research, are co-principal investigators for the study.
“Response teams have faced unprecedented challenges in ongoing efforts to save lives and control the outbreak of Ebola in a highly insecure region of the Democratic Republic of the Congo,” said NIAID Director Anthony S. Fauci, M.D. “Although effective treatments alone will not end this outbreak, the PALM study findings identify the first efficacious treatments for Ebola virus disease and therefore mark a significant step forward in improving care for Ebola patients. We thank the study team for their extraordinary efforts to conduct this landmark trial.”
The study enrolled 681 people with Ebola virus disease between November 2018 and August 2019 at four Ebola treatment centers (ETCs) in the cities of Beni, Butembo, Katwa and Mangina. Staff from The Alliance for International Medical Action (ALIMA), International Medical Corps (IMC), Médecins Sans Frontières/Doctors Without Borders (MSF) and the DRC Ministry of Health implemented the trial at the ETCs with support from Congolese staff, the World Health Organization, the Frederick National Laboratory for Cancer Research and The Mitchell Group.
The study was designed to compare mortality among patients who received one of three investigational Ebola drugs with that from a control group of patients who received the investigational monoclonal antibody cocktail ZMapp, developed by Mapp Biopharmaceutical, Inc. The other therapies were mAb114, a single monoclonal antibody product developed for clinical use by NIAID’s Vaccine Research Center and the INRB and licensed to Ridgeback Biotherapeutics and Mapp Biopharmaceutical; REGN-EB3, a monoclonal antibody cocktail developed by Regeneron Pharmaceuticals, Inc.; and remdesivir, an antiviral drug developed by Gilead Sciences, Inc. The Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services, also has provided support for the development of REGN-EB3, ZMapp and mAb114.
The four therapies are administered as intravenous infusions. REGN-EB3 and mAb114 are administered as single infusions and ZMapp and remdesivir are administered as infusions over multiple days. Study participants also received optimized supportive care, including oral and/or intravenous fluids, electrolyte replacement, monitoring of oxygen levels and blood pressure (with supportive measures as needed), blood transfusions, pain management, and antibiotics and antimalarials as indicated.
The final analysis included 673 participants. The trial began in November 2018 with randomized administration of remdesivir, mAb114 and ZMapp, and the protocol was amended to include REGN-EB3 in January 2019. As a result, the number of outcomes included in the ZMapp comparator group was slightly different for the initial arms (remdesivir and mAb114) relative to the number of outcomes in the ZMapp comparator group for REGN-EB3, based on time of enrollment. Overall mortality was 50% (84/169) in all patients treated with ZMapp and 51% (79/154) in patients who received ZMapp during the time that REGN-EB3 was included as another trial arm. Mortality rates were lower for mAb114 and REGN-EB3 compared to their respective ZMapp cohorts: 35% (61/174) of patients in the mAb114 treatment group and 34% (52/155) of patients in the REGN-EB3 group died by 28 days post-treatment. The mortality rate in the remdesivir treatment group, 53% (93/175), was similar to ZMapp.
Overall, mortality rates were lower in patients who had less virus in their blood at the time of enrollment (19% overall, with 10% for mAb114, 11% for REGN-EB3, 29% for remdesivir and 25% for ZMapp overall). Mortality rates were higher in patients with more virus in their blood at the time of enrollment (76% overall, 70% for mAb114, 64% for REGN-EB3, 86% for remdesivir and 85% for ZMapp). The analysis also showed that patients receiving either mAb114 or REGN-EB3 cleared the virus from their blood more quickly than participants receiving ZMapp.
“These results bring more than hope, they show what powerful tools we have now to save lives in the Democratic Republic of the Congo, and in future Ebola outbreaks. We must make sure everyone affected by the virus knows about these treatments and is able to access them,” said WHO Director-General, Dr. Tedros Adhanom Ghebreyesus.
Investigators note that the trial data demonstrate the importance of early diagnosis and treatment. Patients arriving at the ETC within one day of reported onset of symptoms had a mortality rate of 19%, while patients arriving after five days of symptoms had a mortality rate of 47%. The odds of death increased 11% each day that a person delayed going to an ETC.
“The PALM trial results confirm that it is extremely important for people who have symptoms of Ebola to go to a treatment center as soon as possible to receive advanced supportive care and life-saving therapeutics and increase their chances of survival,” said Professor Muyembe.
All four study drugs were generally well tolerated. There were a total of four serious adverse events that were judged to be potentially related to the experimental drugs. Three of these were in two of the patients who received ZMapp. One was in a patient who received remdesivir.
The authors note that despite encouraging findings regarding mAb114 and REGN-EB3, approximately one-third of patients who received these therapeutics died, highlighting the potential to improve upon these results, whether through further optimization of supportive care, combination therapy using agents with complementary mechanisms of action or other strategies.
“Despite unprecedented challenges—including an unstable electrical power grid and evacuations of staff and patients from treatment centers due to violent attacks—the PALM trial demonstrates that scientifically rigorous and ethically sound clinical research can be conducted during disease outbreaks,” said H. Clifford Lane, M.D., NIAID deputy director for Clinical Research and Special Projects. “We thank the patients and the medical staff in the field and at the treatment sites for their participation and exceptional commitment to the trial.”
The PALM trial is ongoing in an open-label extension phase in which new patients are randomized to receive either mAb114 or REGN-EB3. For more information, visit ClinicalTrials.gov and search identifier NCT03719586.
Reference: S Mulangu et al. A randomized controlled trial of Ebola virus disease therapeutics. The New England Journal of Medicine DOI: 10.1056/NEJMoa1910993 (2019).
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Questions & Answers
PALM Trial of Ebola Therapeutics
On August 1, 2018, the DRC Ministry of Health (MOH) declared the country’s 10th outbreak of Ebola virus disease (EVD). As of November 24, 2019, 2,197 deaths out of 3,303 cases of EVD have been reported in the provinces of North Kivu, Ituri and South Kivu, according to the World Health Organization (WHO). The WHO and the DRC Ministry of Health have coordinated the outbreak response with several international partners. NIAID, along with the U.S. Centers for Disease Control and Prevention, the Biomedical Advanced Research and Development Authority, part of the U.S. Department of Health and Human Services, the Food and Drug Administration, the U.S. Agency for International Development and other U.S. government partners, have provided guidance and support to the multi-sectoral outbreak response.
Yes. All patients with EVD at Ebola treatment centers (ETCs) in the DRC have been offered either mAb114 or REGN-EB3 since the initial results were announced in August 2019. The investigational monoclonal antibody treatments are available through the PALM trial (continuing in an open-label extension phase) or through an expanded access (compassionate use) protocol known as MEURI (Monitored Emergency Use of Unregistered and Investigational Interventions). The preliminary PALM results were immediately shared with the WHO and DRC Ministry of Health when they became available on August 9, so that patients enrolling in MEURI would also receive either mAb114 or REGN-EB3. They have adapted clinical care accordingly, and mAb114 and REGN-EB3 are available at all ETCs. The newly published results have not further changed care guidelines in the DRC.
The trial enrolled 681 patients (335 in Beni, 243 in Butembo, 46 in Katwa and 57 in Mangina), of whom 673 were included in the final analysis. Eight people were excluded from the analysis: one person had a false positive test for Ebola virus infection, and seven people were randomized when the comparator arm, ZMapp, was briefly not available (between January 23 and February 4, 2019) due to distribution issues. Patients of any age, including pregnant women, were included in the study analysis if they tested positive for EVD within three days of enrollment. Newborns also were eligible if the mother had documented infection. Similar treatment effects were seen in all stratified groups, but small sample sizes made it difficult to draw definitive conclusions about the effectiveness of treatments in these subgroups.
- Age range:
- 501 patients (75%) were at least 18 years or older
- 86 patients (13%) were between 5 and 18 years old
- 86 patients (13%) were less than 5 years old
- 5 patients (1%) were less than a week old
- 374 participants (56%) were female, and 17 were pregnant.
- 57 participants (10%) also tested positive for malaria infection.
ZMapp is the only investigational Ebola treatment previously tested in a randomized, controlled efficacy trial. Results from that study, conducted in the United States and West Africa during the 2014-2016 Ebola outbreak, indicated that ZMapp appeared to be beneficial, but the clinical trial ultimately did not enroll enough participants to definitively establish the drug’s efficacy by the time the Ebola outbreak ended. Despite the lack of definitive evidence of efficacy, the DRC investigators determined from the existing clinical trial data for ZMapp that it was a more appropriate control than a placebo in this setting.
The study is monitored by an independent data and safety monitoring board (DSMB). The DSMB conducted a preplanned interim data analysis on August 9, 2019 and observed a clear difference in outcomes in patients receiving REGN-EB3 and mAb114 relative to the control, ZMapp, and no significant difference in outcomes between ZMapp and remdesivir. Based on this review of preliminary data, the DSMB concluded that it was not ethical to continue the trial as designed. It recommended stopping the ZMapp and remdesivir arms and recommended that all patients receive REGN-EB3 or mAb114 in an extension phase of the trial. The study leaders agreed with and implemented this recommendation. All patients who were on remdesivir or ZMapp at the time changes were made were also given the option to receive REGN-EB3 or mAb114.
No. The study compared three investigational treatments to ZMapp, the control arm. The data indicate only that mAb114 and REGN-EB3 are superior to ZMapp and that remdesivir is not superior to ZMapp. The study was not designed for and therefore should not be used for drawing comparisons between the efficacy of mAb114 and REGN-EB3.
EVD is frequently fatal, and before this study, no treatments had been scientifically proven to work. A randomized, controlled clinical trial was the most scientifically rigorous way to determine the safety and efficacy of investigational Ebola treatments. The trial was initiated because it allowed for the most rapid determination of relative safety and efficacy of the investigational treatments and, thus, was the quickest way to provide the most effective treatment to the greatest number of patients.
The study investigators note that vaccination status was not considered when patients were randomized, therefore they cannot draw firm conclusions about the impact of vaccination on mortality. Self-reported vaccination status was recorded from 620 participants. Of this group, 25% (155/620) reported receiving an Ebola vaccine (rVSV-ZEBOV, also known as V920, developed by Merck); 39% (60/155) of this group reported receipt of the vaccine 10 days or more before onset of clinical symptoms. Patients who noted they had received the vaccine were more likely to seek treatment soon after onset of symptoms and generally had more favorable prognostic profiles at baseline.