The PALM trial evaluated the safety and efficacy of several experimental treatments for Ebola in the Democratic Republic of Congo.
In August 2018, an Ebola virus disease outbreak was declared in the Democratic Republic of Congo (DRC), the second largest since the initial description of the Zaire strain in 1976. In October 2019, the World Health Organization concluded that the outbreak was still considered to be a Public Health Emergency of International Concern.
Several experimental therapeutics for Ebola have been rising through the stages of development. Results from a randomized, controlled trial evaluating different therapeutics were published in The New England Journal of Medicine. The PALM trial (Pamoja Tulinde Maisha [“Together Save Lives” in the Kiswahili language]) evaluated the safety and efficacy of these treatments in the context of the ongoing Ebola outbreak in the DRC.
In the trial, the combination of standard care plus either the single monoclonal antibody, Mab114, or the triple monoclonal antibody, REGN-EB3, was found to superior to standard care plus the triple chimeric monoclonal antibody ZMapp.
A total of 681 patients were enrolled between November 20, 2018 and August 9, 2019. After August 9, patients were assigned only to the Mab114 and REGN-EB3 treatment groups for the remainder of the trial, after interim analysis showed their superiority to ZMapp and remdesivir with respect to mortality.
All patients received standard care which consisted of correction of hypoglycemia and electrolyte imbalances, intravenous fluids, daily clinical laboratory testing, as well as administration of broad-spectrum antibiotic agents and antimalarial agents.
Participants were randomly assigned in a 1:1:1:1 ratio to the MAb114, REGN-EB3, remdesivir, and ZMapp groups. Since REGN-EB3 was added in a later version of the protocol, data was compared via a ZMapp subgroup of those in the ZMapp group enrolled at or after the time REGN-EB3 was added.
Patients were assessed for eligibility using a reverse-transcriptase-polymerase-chain reaction assay to detect RNA of the nucleoprotein of Ebola virus. Patients of any age, including pregnant women, were eligible if they had not received other investigational treatment agents (apart from experimental vaccines) within the past 30 days.
Trial-group assignments were made in sequentially numbered envelopes, distributed to trial sites to be opened at time of enrollment. Data were recorded on paper case-report forms that were digitally sorted into electronic patient folders entered into the web-based REDCap database.
The primary end point examined was death at 28 days. At 28 days, death occurred in 61 of 174 (35.1%) patients in the MAb114 group and 52 of 155 (33.5%) patients in the REGN-EB3 group.
In comparison, at the same point, death had occurred in 84 of 169 (49.7%) of patients in the ZMapp group. In the ZMapp subgroup, 79 of 154 (51.3%) patients died.
Lower baseline values for viral load and for serum creatinine and aminotransferase levels correlated with improved survival, as did a shorter duration of symptoms prior to admission.
Because 97% of deaths in the trial occurred within 10 days after enrollment, study authors wrote that the efficacy of MAb114 and REGN-EB3 as compared to ZMapp and remdesivir might be partially attributable to the fact that full treatment courses of the former were administrable in 1 dose, whereas ZMapp and remdesivir required multiple infusions.
Further evidence supporting this observation was found in the fact that patients in the MAb113 and REGN-EB3 groups had faster rates of viral clearance.
Several challenges impeded investigators. Authors reported that the trial took place in a region of the DRC with mistrust of the government and the international response to the Ebola outbreak, an unstable power grid, transportation difficulties, and regional violence.
The trial had to be temporarily halted at 2 locations due to violence directed at them by local community or paramilitary groups suspicious of the facilities.
“This trial showed that it is possible to conduct scientifically rigorous and ethically sound research during an outbreak, even in a conflict zone,” study authors wrote, crediting staff and patients who participated in the trial through challenging circumstances.