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Excerpt
On April 17, 1998, Glaxo Wellcome (Research Triangle Park, NC) suddenly terminated its international trial of L-NG-methylarginine hydrochloride, a nonselective nitric oxide synthase inhibitor, for the treatment of patients with septic shock. This experimental agent acts like a vasopressor by restoring vasomotor tone. Interim analysis of the first 522 patients in this trial showed a significant increase in the mortality rates of patients receiving the experimental agent (Steve Grossman, MD; Glaxo Wellcome; press release).
The 1990s has been a decade which has brought about a greater understanding of the inflammatory response during overwhelming infection and, as a result, has heightened expectations at the bedside. Unfortunately, these expectations have been met with endless disappointment in the marriage of bench biology with sepsis research in the clinical arena. Two other trials of septic shock in this decade, the Immunex Phase II study [1] of the p80-soluble receptor to tumor necrosis factor (TNF) and Centocor's Phase IIIb antiendotoxin trial [2] of HA-1A for Gram-negative bacteremia, also resulted in excessive mortality rates for patients receiving the experimental agent. No large human study of nonglucocorticoid inflammatory modulation has shown significant benefit in septic patients. Zeni et al. [3] performed a meta-analysis of 18 clinical trials [4-20] of nonglucocorticoid anti-inflammatory agents. The analysis did not demonstrate a statistical benefit to immunomodulation, although a small beneficial treatment effect might possibly exist (odds ratio 1.11; 95% confidence interval 0.99 to 1.23; p = .07). Since publication of that assessment, results of three other Phase III trials have been announced. Efforts to neutralize TNF included anti-TNF studies by Knoll (Ludwigshafen, Germany) in Europe (RAMSES; severe sepsis or septic shock [21]) and Bayer (West Haven, CT) in North America (NORASEPT II; septic shock [22]). As well, Hoffman-LaRoche tested a p55-soluble TNF-receptor in Europe and North America (Tenefuse; severe sepsis [23]). All of these failed to show clinical benefit. Moreover, two additional Phase III trials have been discontinued before study completion when interim analysis showed little likelihood of proving clinical benefit (Taurolidine, Carter Wallace, Nutley, NJ; E5 anti-endotoxin, Pfizer, New York, NY).
Altogether, 28 prospective, controlled studies of human sepsis have been conducted during this decade. Among the 26 fully completed investigations are 22 studies of nonglucocorticoid anti-inflammatory agents [1,4-23] and four antiendotoxin studies [2,24-26]. Three studies demonstrated excessive mortality rates and 23 others showed no benefit for patients randomized to the experimental agent. These investigational outcomes beg the question: "If the best we have been able to offer our critically ill patients who are willing to submit to sepsis research is no benefit or an increase in mortality rate, at what point is it no longer ethical to pursue this line of investigation?" I wonder if it isn't time to rethink the present approach to large human sepsis trials. Dare I ask it (gulp), is it time for a moratorium?
Is It Ethical to Conduct Human Sepsis Trials in the Present Manner? The overall mortality rate of sepsis in this decade is estimated to be [similar]36% [3]. The most recent and largest trial ever of septic shock established a placebo mortality of 43% [22]. These dreadful outcomes with conventional care dictate that sepsis research be continued.
What is wrong, and possibly unethical, is to repeat the same investigative format with the same experimental flaws inherent in the studies of this decade. We must make substantial changes in the way we study new inflammatory modulators if there is to be any hope of demonstrating efficacy in the future and not repeating the failures of the past.
