ABSTRACT
Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.
ABSTRACT
COVID-19 has become a global pandemic, and an effective vaccine is needed. During the outbreak, the urgency for developing candidate vaccines has brought distinct challenges to clinical development. An efficacy trial, which measures whether the vaccine reduces the incidence of disease, is ordinarily required to fully evaluate vaccine efficacy. However, emergency use may be possible if promising immunogenicity results are observed. A ring vaccination trial, which recruits subjects connected to a known case either socially or geographically, is a solution to evaluate vaccine efficacy and control the spread of the disease simultaneously although its conduct is challenging. Nevertheless, when COVID-19 becomes a recurrent epidemic, an 'individual-level' efficacy trial is preferred. Innovative statistical designs, including seamless design, platform trial, master protocol design, are helpful to accelerate clinical development. A seamless Phase I/II design has been applied in multiple COVID-19 vaccine studies to date. However, Phase II/III design should be done very carefully. The control of type I error, maintaining trial blinding and statistical methods leading to unbiased estimates should be pre-specified in the clinical protocol. A Data Safety Monitoring Board is especially important, given the need to assure an adequate level of safety when society want a safe and effective vaccine.