Treatment of severe sepsis in patients with highly elevated IL-6 levels with anti-TNF monoclonal antibody MAK 195F: The Ramses study

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This prospective placebo-controlled double-blind clinical study investigated the efficacy of the monoclonal anti-TNF antibody MAK 195F (Afelimomab) compared to placebo in patients suffering from severe sepsis and septic shock with highly elevated IL-6 levels. Patients were stratified at entry into the trial by a semi-quantitative rapid stick test into those with IL-6 serum levels and below 1000 pg/ml serum. High IL-6 patients were randomised to receive either MAK 195F as 9 single doses for 1 mg/kg in 8 h intervals or placebo as additive treatment and followed for 28 days. Low IL-6 patients were not randomised and only followed for survival.

Altogether 944 patients were enrolled into the study before the trial was stopped prematurely. This early termination was based on the results of a planned interim analysis which releaved that it was very unlikely that the study would finally end up with a positive result when completed as planned.

From those 944 patients 446 were stratified to be randomised, 224 received MAK 195F and 222 received placebo, 498 patients were not randomised. Mortality rates in the randomised patients was 57.7% in the placebo-treated group and 54.0% in the MAK-treated group. The mortality rate in the non-radomised patients was 39.6%. Whereas the mortality difference between the two randomised patient groups did not reach statistical significance, the difference between the randomised and non-randomised patients was highly statistically significant (P < 0.001).

In conclusion, this study demonstrated that the innovative IL-6 rapid stick used to stratify the study patients was a powerful tool to identify patients with a high mortality risk in sepsis. However, the study failed to proof the efficacy of MAK 195F to reduce mortality in septic patients with highly elevated IL-6 levels. A similar study is currently still ongoing in North-America.