International sepsis trial (INTERSEPT): role and impact of a clinical evaluation committee.
OBJECTIVE
Several large clinical trials have recently evaluated a variety of potential therapeutic interventions for sepsis and have yielded negative results based on analyses of intention-to-treat cohorts. The present study was undertaken to evaluate the importance of a Clinical Evaluation Committee.


METHODS
Prospective, double-blind evaluation of a prospective, controlled, double-blind, randomized, multinational trial.


METHODS
Forty medical centers.


METHODS
Five hundred fifty-three infused patients with severe sepsis and septic shock.


METHODS
As part of an international trial (INTERSEPT) of antitumor necrosis factor therapy, a Scientific Extramural Review Committee prospectively defined and excluded patients with confounding events that objectively interfered with the potential of any intervention for sepsis to exercise its therapeutic effect. These confounding events included inappropriate antimicrobial therapy, inadequate medical-surgical management, underlying disorders, and forgoing life-sustaining therapies before management had failed. Patients who met all inclusion and exclusion criteria and who had no confounding events were defined as the Scientific Extramural Review Committee group.


RESULTS
Five hundred fifty-three patients were enrolled in INTERSEPT. Seventy-seven patients did not meet inclusion and exclusion criteria. Sixty patients had confounding events, including inappropriate antimicrobial therapy (n = 28), inadequate medical-surgical management (n = 16), underlying disorders (n = 17), and forgoing life-sustaining therapies (n = 7). Four hundred sixteen patients were in the Scientific Extramural Review Committee group and their mortality rates were different from the mortality rates of the intent-to-treat cohort. In the intent-to-treat analysis among shock patients, low-dose anti-tumor necrosis factor reduced 28-day mortality by 14.5% (p = .34), whereas in the Scientific Extramural Review Committee group, the study drug reduced mortality by 26.5% (p = .16). More patients in the high dose anti-tumor necrosis factor treatment arm (31/176) were in the invalid Scientific Extramural Review Committee group than in the other two arms (16/157 and 13/143, respectively, p < .05).


CONCLUSIONS
In large trials of sepsis, in addition to analyzing the intent-to-treat cohort, patients in compliance with the protocol and with no confounding events should also be analyzed. These results should assist in determining whether treatment groups are comparable and provide a greater likelihood of demonstrating the potential efficacy of a new therapy for sepsis. A Clinical Evaluation Committee is important to properly assess a clinical sepsis trial.
Sprung
C L
CL
Hadassah University Medical Center, Hebrew University of Jerusalem, Israel.
Finch
R G
RG
Thijs
L G
LG
Glauser
M P
MP
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000592:standards*; D015986:Confounding Factors, Epidemiologic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010043:Outcome and Process Assessment, Health Care / Q000592:standards*; D011367:Professional Staff Committees; D011446:Prospective Studies; D015203:Reproducibility of Results; D012107:Research Design; D012772:Shock, Septic / Q000401:mortality / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha