Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.

OBJECTIVE: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis. SETTING: Ninety-one academic medical center intensive care units in North America and Europe. PATIENTS: Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. INTERVENTIONS: Patients were randomized to receive either rhIL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg/hr) or placebo. MEASUREMENTS AND MAIN RESULTS: The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study. CONCLUSIONS: A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group.

OBJECTIVE: To preliminarily evaluate the safety and efficacy of different dose levels and dosing frequencies of recombinant human interleukin-1 receptor antagonist (rHuIL-1Ra) in the treatment of patients with rheumatoid arthritis (RA). METHODS: One hundred seventy-five patients with active RA were enrolled in a randomized, double-blind trial of rHuIL-1Ra administered by subcutaneous injection. There were 9 treatment groups in the trial. During the initial 3-week treatment phase, patients were treated with 20, 70, or 200 mg rHuIL-1Ra, administered either once, 3 times, or 7 times per week, followed by a 4-week maintenance phase, during which all patients received the treatment-phase dose once per week. To maintain the blindness of the study, patients received daily injections of either rHulL-1Ra or placebo on the days rHuIL-1Ra was not administered. RESULTS: Recombinant HuIL-1Ra was well tolerated. The most frequent adverse event was injection-site reactions, which were reported in 62% of patients and caused 8 patients (5%) to withdraw prematurely from the study. Five patients (3%) developed serious adverse reactions unrelated to dose or dosing frequency. Due to the lack of a placebo arm and to the multiple small treatment groups, a definitive statement regarding efficacy could not be made. However, by the end of the 3-week treatment phase, daily dosing appeared more effective than weekly dosing when assessed by the number of swollen joints, the investigator and patient assessments of disease activity, pain score, and C-reactive protein levels. CONCLUSION: These preliminary data suggest that rHuIL-1Ra may be safely administered by subcutaneous injection to RA patients. The frequency of dosing appears to be important in determining clinical response, with daily administration providing the most benefit. A placebo-controlled trial is in progress to further assess the clinical usefulness and to better define appropriate doses of rHuIL-1Ra in patients with RA.

Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis.

Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.

Arbaprostil's [15(R)-15-methyl PGE2] effects on intrauterine pressure in the nonpregnant and pregnant human female--a report of four clinical trials.

Four clinical trials evaluating arbaprostil's effects on the human uterus are reported. The initial two trials measured intrauterine pressures in nonpregnant and pregnant human females following arbaprostil doses of 10, 25, and/or 50 mcg. No statistical differences were found at any dosage level in either study for average uterine resting pressures, average peak pressures, the number of contractions or Montevideo units. Subsequently, two trials determined the abortifacient potential of arbaprostil in pregnant women during the first trimester. The first utilized total daily doses of 400 and 800 mcgs. while the second used total daily doses of 1200 and 1600 mcgs. Vaginal spotting was noted in one woman receiving 400 mcgs, three receiving 1200 mcgs. and in two receiving 1600 mcgs. One episode of moderate bleeding was seen in the latter study. Based on these studies, arbaprostil exhibits little potential for inducing abortifacient activity at these dosages in these patient populations.

A multiclinic trial evaluating arbaprostil [15(R)-15-methyl prostaglandin E2] as a therapeutic agent for gastric ulcer.

A randomized, double-blind, placebo-controlled, multiclinic trial evaluated arbaprostil [15(R)-15 methyl prostaglandin E2] for the treatment of acute gastric ulcer, achieving an overall enrollment of 124 patients (of which 113 were considered evaluable). This 6-wk trial used an arbaprostil dose of 10 micrograms q.i.d., which has little gastric acid antisecretory activity. Endoscopies were performed after 21 and 42 days of treatment, at which times the arbaprostil and placebo healing rates, respectively, were 6/59 (10.2%) and 4/53 (7.6%) on day 21 and 25/59 (42.4%) and 16/50 (32.0%) on day 42. No significant differences between the treatment groups were found for pain relief, antacid consumption, and mucosal healing. This trial documents that a 10-micrograms dose of arbaprostil (which may be considered cytoprotective because of its small effect on gastric acid secretion), although safe and associated with no side effects, is not efficacious in healing acute gastric ulcers.

Failure of a cytoprotective dose of arbaprostil to heal acute duodenal ulcers. Results of a multiclinic trial.

Previous therapeutic trials with prostaglandins have shown them to be effective in healing duodenal ulcers when used at doses that are highly effective suppressors of gastric acid secretion. We undertook this trial to determine if a cytoprotective dose of arbaprostil (10 micrograms q.i.d. for 4 wk) would also be efficacious in this disease state. Eighty-two patients between the ages of 19 and 72 yr with endoscopically documented duodenal ulcers were entered into this randomized double-blind placebo-controlled trial. The patients were monitored with biweekly endoscopies and laboratory examinations, weekly interviews during the period when drug was administered, and a follow-up interview plus laboratory examinations 1 wk after drug administration was completed. No statistically significant differences between the arbaprostil and placebo treatment groups were found for ulcer healing rates, pain relief, antacid consumption, side effects, or laboratory examinations. It is presumed that this prostaglandin may not have sufficient duodenal cytoprotective capacity to effectively heal duodenal ulcers, or that some suppression of gastric acid secretion may be required to achieve significant clinical efficacy.

Lack of effect of arbaprostil on the human non-pregnant uterus.

Arbaprostil ((15R)-15-methyl Prostaglandin E2) is being studied for the treatment of gastrointestinal illness. To determine its effect on the human uterus, eight sterilized pre-menopausal women were studied during the proliferative phase of their menstrual cycle. Using a microtransducer catheter, intra-uterine pressures were recorded for at least 30 minutes prior to and 2 hours after arbaprostil administration. Each subject was studied four times, at 48-hour intervals, receiving in a double-blind manner; 0, 10, 25, and 50 micrograms. Arbaprostil at does up to 50 micrograms was found not to have any clinically significant effects on the non-pregnant human uterus.