Replies to post #6004 on GTC Biotherapeutics (fka GTCB)

[DewDiligence]

Predicted-survival range in phase-2 DIC trial:

>limiting inclusion criteria to those with intermediate prognosis (i.e. recognizing that those with less severe disease and limited organ dysfunction will survive regardless, and those with the most severe cases will die regardless of treatment stratification)<

This key design feature of Leo’s phase-2 trial has been overlooked by the ATryn-in-DIC skeptics, IMO. Patients admitted into Leo’s trial must have predicted survival—based on an industry-standard model—in the 40-70% range. (I.e., predicted mortality must be 30-60%). For patients with predicted survival <40% or >70%, including them would place an undue burden on the statistical power of the trial for the reasons you cited.

If the 40-70% predicted-survival range works well in phase-2, I expect it will be expanded somewhat in phase-3, where the statistical power will be greater. Regards, Dew

[DewDiligence]

The Response of Antithrombin Activity After Supplementation
Decreases in Proportion to the Severity of Sepsis and Liver Dysfunction

[If I’m reading this study correctly, it loosely corroborates the notion that AT works best in sepsis patients with a midrange prognosis (#msg-25154549 item #2).]

http://www.ncbi.nlm.nih.gov/pubmed/18496242

>>
Shock. 2008 May 13.

Hayakawa M, Sawamura A, Yanagida Y, Sugano M, Hoshino H, Gando S.

Emergency and Critical Care Center, Hokkaido University Hospital, Sapporo, Japan.

The decrease in the antithrombin III activity is thought to result from consumption by ongoing coagulation, degradation by neutrophil elastase, capillary leak syndrome, and impaired synthesis. A retrospective data analysis of patients with sepsis was conducted to investigate the response of antithrombin III activity after supplementation in patients with sepsis, and to determine what factors affect the response of antithrombin III activity.

The study included 42 patients with sepsis, 75 patients with severe sepsis, and 65 patients with septic shock, who were administered antithrombin III. Antithrombin III activity, platelet counts, coagulation, and fibrinolytic markers were collected before administration and 24 h after the supplementation. In the patients with septic shock, the response of antithrombin III activity after supplementation was 0.37% +/- 1.21%/IU per kg body weight, which was significantly lower in comparison with those in the patients with sepsis (1.81 +/- 1.75; P < 0.001) or severe sepsis (1.36 +/- 1.65; P < 0.001). The patients with liver dysfunction had significantly lower response to antithrombin III activity than that of the patients without liver dysfunction (P<0.0001).

A stepwise multiple linear regression analysis revealed that the severity of sepsis and liver function were independent predictors for the response to antithrombin III activity. These results suggest that the response to antithrombin III supplementation may be affected by both a systemic inflammation and impaired synthesis in patients with sepsis.
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