SummaryBackgroundInfluenza causes significant morbidity and mortality despite currently available treatments. Anecdotal reports suggest plasma with high antibody titers towards influenza may be of benefit in the treatment of severe influenza.MethodsWe conducted a randomized, open-label, multicenter phase 2 trial at 29 academic medical centers in the United States to assess the safety and efficacy of anti-influenza plasma with hemagglutination inhibition (HAI) antibody titers of ≥ 1:80 to the infecting strain. Hospitalized children and adults (including pregnant women) with severe influenza A or B (defined as hypoxia or tachypnea) were randomly assigned to receive either 2 units (or pediatric equivalent) of anti-influenza plasma plus standard care (P+S), versus standard care alone (S), and were followed for 28 days. The primary endpoint was time to normalization of patients’ respiratory status (respiratory rate of ≤ 20 for adults or age defined thresholds of 20–38 for children), and a room air saturation of oxygen ≥ 93%. ClinicalTrials.gov Identifier: NCT01052480FindingsBetween January 13, 2011 and March 2, 2015, 113 participants were screened, and 98 were randomized. Of the participants with confirmed influenza, 28 of 42 (67%) of P+S participants normalized their respiratory status by Day 28, as compared to 24 of 45 (53%) of S participants (p=0·069). The estimated hazard ratio comparing P+S to S was 1·71 (95% CI: 0·96 to 3·06). Six participants died, 1 (2%) and 5 (10%) from the P+S and S arms respectively (p=0·093). P+S participants had non-significant reductions in days in hospital (median 6 vs. 11 days, p=0·13) and days on mechanical ventilation (median 0 vs. 3 days, p=0·14), and significantly improved clinical status at Day 7 (p=0·020). Fewer P+S participants experienced SAEs compared to S recipients (20% vs. 38%, p= 0·041), the most frequent of which were acute respiratory distress syndrome (1 [2%] vs 2 [4%]) and stroke (1 [2%] vs 2 [4%]).InterpretationResults from this Phase II randomized trial of immune plasma for the treatment of severe influenza provides support for a possible benefit of immunotherapy across the primary and secondary endpoints. A Phase III randomized trial is now underway to further evaluate this intervention.

High- and medium-dosage clobazam was estimated to be more efficacious than other LGS treatments. Our analysis relied on published data and could not draw on direct head-to-head data of clobazam with alternatives. Further comparative research is ongoing to assess the usefulness of clobazam for LGS.

that accompanied our report of a placebo-control monotherapy trial of oxcarbazepine for partial seizures 2 carries forward the recent spirited discussion in the literature about the design and importance of monotherapy studies in epilepsy. [3][4][5] However, we feel compelled to respond to their assertions concerning the clinical value and ethics of our study.Was our study clinically valuable? Absolutely. Because of its placebo-controlled design, our study convincingly established the antiseizure activity of oxcarbazepine. This demonstration has significant value because proof of efficacy is justifiably essential for a drug to be licensed in the United States. In addition, our study showed that oxcarbazepine can be safely titrated over one day and that its antiseizure effects begin rapidly. This finding is meaningful to clinicians because of the paucity of other controlled studies that show antiepileptic drug (AED) efficacy in an acute setting.Was our study ethical? The principal investigators, coinvestigators, and sub-investigators, all of whom were associated with leading academic medical centers, as well as their institutional review boards and their clinical research center scientific advisory boards (where applicable) would not have otherwise performed or approved this study. However, Chadwick and Privitera argue that our study compromised two of Beauchamp and Childress' principles of medical ethics-beneficence and nonmaleficence 6 -and their balance, or equipoise. 7 We strongly disagree. Equipoise existed in our study because beneficence for oxcarbazepine had not been previously established, in our opinion. Yes, oxcarbazepine is indeed widely licensed for the treatment of epilepsy in Europe and is structurally similar to carbamazepine. But in this era of evidence-based medicine, how convincing is the previously published data that oxcarbazepine is effective?As clinicians, we agree that comparative monotherapy trials, such as the widely influential Veterans Administration Cooperative Study, 8 are more relevant to the practical day-to-day care of patients than placebo-controlled trials such as ours. We further agree that more such studies are needed. However, the study design of comparative trials must be suitable to allow the antiseizure effects of each treatment to be observed. Otherwise, doctors can not reasonably conclude that a new treatment is more or less effective than an old one.Whether the published double-blind, comparative oxcarbazepine studies satisfy this study design requirement is debatable. They consisted of trials in which patients were randomized to oxcarbazepine or existing standard treatment, and then the proportions of seizure-free patients during the treatment period were compared. 9-13 None of these studies were placebo-controlled, and none showed that oxcarbazepine had superior efficacy compared with another active treatment. Most significantly, the actual effectiveness of oxcarbazepine or the other treatments relative to the underlying likelihood of spontaneous seizure remission dur...

No abstract