Table 3 Design and outcomes in a randomized trial and non-randomized studies of anti-Ebola therapies
From: Anti-Ebola therapy for patients with Ebola virus disease: a systematic review
Agent Citation | Primary outcome Selected details of design | Dates of study Reason for termination | Mortality | Adverse events |
|---|---|---|---|---|
Randomized clinical trial | ||||
ZMapp PREVAIL II Writing group, 2016 [24] | 28-day mortality • Adaptive design: plan to update standard-of-care treatment with the investigational drug, if efficacious in interim analysis • All patients recruited in Guinea received favipiravir as standard of care • 6 randomization strata: baseline PCR CT value (≤22 vs. > 22) and location (Liberia/Sierra Leone vs. Guinea vs. USA); in analysis, location strata changed to Liberia/Sierra Leone/USA vs. Guinea • Planned maximum sample size, n = 200 (100 per group) | March–November 2015 Trial closed in January 2016 after affected countries declared nearly Ebola free | • 28-day mortality: 22% (8/36), intervention 37% (13/35), control • Bayesian RD − 14% [95% CrI, −34% to 6%] • Bayesian RR 0.62 [95% CrI, 0.29 to 1.24] • Posterior probability that intervention was superior to control, 91.2% (below pre-specified probability threshold of 97.5%) | • Serious adverse events: 31% (11/36), intervention 37% (13/35), control; p = 0.62 • One serious adverse event (hypertension) judged to be related to the ZMapp infusion |
Non-randomized single-arm intervention study with concurrent controls | ||||
TKM-130803 Dunning et al., 2016 [25] | 14-day survival, excluding deaths within 48 h of ETC admission • Concurrent observational cohort for patients who did not meet additional criteria for drug infusion • Plan for randomization of eligible patients to intervention vs. control arm if number of eligible patients exceeded available treatment beds; this scenario did not happen • Planned maximum sample size, n = 100 | March–June 2015 Study closed after futility boundary reached | • 14-day mortality (intervention): 75% (9/12) 79% (11/14), if the additional 2 patients who died within 48 h are included • Probability of 14-day survival, given 48-h survival, 0.27 [95% CI, 0.06 to 0.58] • 2 of 3 patients in the observational cohort died | One patient had worsening tachypnea within 48 h of the second TKM-130803 infusion; event felt to be compatible with progression of EVD |
Convalescent whole blood Sahr et al. 2017 [26] | Not stated; mortality and other outcomes reported • Patients who did not consent to intervention were recruited into control arm • No sample size calculation | December 2014–April 2015 Reason for stopping not stated | • Mortality: 28% (12/43), intervention 44% (11/25), control • One patient who received intervention dropped out and is excluded from the denominator • ORsurvival with intervention, 2.3 (95% CI, 0.8 to 6.5) | None |
Interferon β-1a Konde et al. 2017 [27] | Clearance and/or reduction in viral RNA from day 1 to day 10, as determined by PCR and/or quantitative real time PCR • 21 control patients admitted to the same ETC during the same time period as the treated patients • 17 more control patients selected; they matched treated patients on specified criteria and received care in a Guinean ETC; time period of treatment of these additional controls not stated • ‘sample size of 30–50 chosen to assess feasibility’ | March–June 2015 Reason for stopping not stated | • 21-day mortality: 33% (3/9), intervention 84% (32/38), all controls 81% (17/21), controls from same ETC log-rank p = 0.026 comparing intervention to 21 controls • Multiple regression models reported ORmortality with intervention, adjusted for CT, 0.13 (p = 0.022; CI not reported) | Not reported |
Non-randomized, single-arm, intervention study with historical control | ||||
Convalescent plasma van Griensven et al., 2016 [28] | 14-day mortality (including deaths from days 3 to 16 after PCR confirmation of EVD) • Control patients treated in the same ETC before the start of the study • Planned sample size, n = 260 (130 per group) | February–August 2015 Study closed in July 2015 due to low caseload | • Mortality 3–16 days after diagnosis: 31% (26/84), intervention 38% (158/418), control 34% (30/88), intervention, if 15 patients who also received it are included, of whom 4 died before day 3 • ORmortality with intervention, adjusted for age and CT, 0.88 (95% CI, 0.51 to 1.51) | • No serious adverse events • 8 patients had adverse reactions during or early after the infusion 5 increase in temperature 4 itching or skin rash 1 nausea 2 reactions requiring reduction in infusion rate |
Favipiravir Sissoko et al., 2016 [29] | 14-day mortality (changed to ‘on-trial mortality’ to include 1 patient who died at day 17) • Control patients (n = 540) from database of MSF ETCs in forested Guinea • Initial sample size, n = 180 (60 per group defined by age and time of treatment after symptom onset; definition of strata changed to include age and CT) | December 2014–April 2015 Study closed due to low caseload | Mortality: 54% (60/111), intervention 58% (315/540), control 51% (64/126), intervention, if 15 patients who also received it are included, of whom 4 died Adjusted analysis not reported | • Vomiting within 30 min of pill intake occurred in 30 instances (2%) in 21 patients. • No severe adverse events |
Favipiravir Bai et al., 2016 [30] | Mortality (time not specified) • Intervention patients treated 1–10 November 2014 • Control patients treated in the same ETC, 10–30 October • Intravenous fluids limited in the study ETC | 10 October-10 November 2014 Study closed when research team rotated out of ETC | Mortality: 44% (17/39), intervention 65% (55/85), control [unadjusted p = 0.027] Adjusted analysis not reported | Not reported |
Non-randomized single-arm intervention study without controls | ||||
Brincidofovir Dunning et al. 2016 [31] | 14-day mortality • No control group • Planned maximum sample size, n = 140 | January 2015 Study closed because manufacturer stopped participation in all studies of brincidofovir for EVD | 14-day mortality: 100% (4/4) | • No serious adverse reactions • No serious unexpected serious adverse reactions • Concern that intervention might have contributed to persistent diarrhea in 1 patient |
Retrospective cohort study | ||||
Artesunate-amodiaquine Gignoux et al. 2016 [32] | Mortality (time not specified) Cohort study based on natural experiment: 71 patients prescribed artesunate–amodiaquine because of shortage artemether–lumefantrine (given to 194 patients) | June–October 2014 Study closure: not applicable | • Mortality: 50.7% (36/71), artesunate-amodiaquine; 64.4% (125/194), artemether-lumefantrine; 65.1% (41/63), no anti-malaria drugs • Adjusteda RRmortality 0.69 [95% CI 0.54 to 0.89] | Not described |