A randomized, double-blind, placebo-controlled phase IIIa study of bIAP, an anti-inflammatory moiety, in patients undergoing combined aortic valve replacement and coronary artery bypass grafting.

It has been established that cardiac surgery is associated with a post surgical
systemic inflammatory response (SIRS), the impact of which is subject to the
immunological vigilance of the patient but also to surgical conditions. Thus it
is generally accepted that the incidence of SIRS is correlated positively to
the duration of perfusion time. In CABG, a relatively short-duration surgery,
where perfusion time is limited to about one hour we have shown in the first
APPIRED-I study that significant postsurgical inflammation is observed only in
a specific relative small group of placebo-treated patients but not in patients
treated with alkaline phosphatase. Specifically: solely in placebo-treated
patients a significant subgroup was identified that responded in high post
surgical TNF-*, whereas in alkaline phosphatase (AP) treated patients such a
TNF-* response was not identified. Increased systemic TNF-* levels are reported
to be associated with vascular injury and ischemic damage. On the basis of the
APPIRED-I study outcome, where patients for elective CABG, with relatively low
perfusion and cross clamp time were included, it is expected that in procedures
with longer cross clamp and perfusion time, like combined aortic valve
replacement and CABG, patients will benefit more from alkaline phosphatase
treatment.

Primary Objective:
The objective of this study is to determine the efficacy of bIAP as a
prophylactic agent against inflammation-mediated complications from more
invasive cardiac surgery, aortic valve surgery and CABG with
cardiopulmonary-bypass time of longer than 1 hour.
Primary study endpoint is the postulated reduction of the number of
post-surgical inflammatory response in the bIAP-treated patient group as
compared to the placebo-treated group. Inflammatory response, in the sense of
this study, is indicated by an increased TNF-* level of at least 10 pg/ml above
the pre-surgical level, which is normally followed by an increase of IL-6 and
IL-8.

Initially a mono-centre prospective, randomized, double-blind,
placebo-controlled intervention trial involving a max of 50 patients. As of
March 2012 ZOL-Genk (Belgium) participates in this study. From Q4, 2012 MUMC
(Maastricht) likely will be participating as well (pending approval).
THe total study may involve up to 150 patients, of which first 50 patients and
interim evaluation are expected ultimo Q4 2012.

Patients receive intravenous as a bolus either placebo or bIAP (alkaline
phosphatase, 1000 IU) just prior to surgery followed by a 40 IU/kg bIAP/placebo
infusion during 8 hours.

So far no identified risk is associated with the therapeutic use of
intravenously or orally administered alkaline phosphatase. Burden to the
patient is limited to disposing additional blood samples. Patients will be
asked to allow blood sampling during a time interval of 5 days, most of which
is during the time that intravenous lines are available during surgery and
recuperation time at the ICU. A total of 12 samples will be collected, of which
5 samples are drawn by syringe. It is estimated that a total of 116 ml blood
is required for the study, which does not constitute a health risk to the
patients. Furthermore, the patients will be called for a follow-up visit at one
month post-surgery, at which time data on concomitant medications and adverse
events will be recorded.