Efficacy and Safety of Bovine Intestinal Alkaline Phosphatase (bIAP) During Heart Surgery (APPIRED-II)

A Randomized, Double-blind, Placebo-controlled Phase IIIa Study on bIAP, an Anti-inflammatory Moiety, in Patients Undergoing Combined Aortic Valve Replacement and Coronary Artery Bypass Grafting

This multi-centre prospective, randomised, double-blind, placebo-controlled study is designed to evaluate the efficacy and safety of bovine intestinal alkaline phosphatase (bIAP) in reducing the pro-inflammatory post-surgical responses and thereby preserving organ functions in patients undergoing invasive cardiac surgery: combined aortic valve replacement and coronary artery bypass grafting.

Study Overview

• Status: Completed
• Conditions: Inflammation
• Intervention / Treatment: Drug: bIAP bolus and 8h infusion; Drug: placebo bolus and 8h infusion

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Eindhoven, Netherlands, 5623 EJ
    • Catharina Ziekenhuis, Dept. CardioThoracic Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or non-pregnant, non-lactating female patients of any race in the ages of >18 years.
• Patients scheduled for combined aortic valve replacement and CABG surgery.
• Patients who have given written informed consent prior to participation in the trial and who undertake to comply with the protocol.

Exclusion Criteria:

• Patients who are unwilling or unable to be fully evaluated for follow-up.
• Patients who have base AP levels at > 125 IU/L, or levels < 30 IU/L (ammediol, DEA (diethanolamine) units)
• Patients who show pre-operative infections or who are suspected of endocarditis or systemic infection.
• Patients who refuse to accept medically-indicated blood products.
• Patients who have evidence of significant hepatic disease, including history of clinical signs or laboratory values of total bilirubin > 34.2 µmol/L (> 2.0 mg/dL), ALT (>120) or AST (>135) corresponding to > 3X upper limit of normal.
• Patients who received investigational drugs in the 30 days prior to study drug administration, or are currently participating in a study during which the administration of investigational drugs within one month is anticipated.
• Patients who require pre-operative ventilatory support.
• Patients who have renal insufficiency (history of creatinine >177mol/L or >2.0 mg/dL) or chronic renal failure requiring dialysis.
• Patients who are planned to receive leukocyte-depletion filtration as part of the bypass circuitry.
• Patients with severe neurological deficits.
• Patients who have a recent history of drug or alcohol abuse.
• Patients with a diagnosis of idiopathic thrombocytopenia.
• Patients with a history of cancer who have received chemotherapy or radiation therapy within the past 3 months. Patients receiving only adjuvant hormonal therapy are not excluded.
• Patients who are scheduled to receive "stress doses" of glucocorticoids (i.e., doses >2 mg/kg/day of methylprednisolone or equivalent) prior to, during or following surgery.
• Patients who are vegetarians or veganists or those patients that may be expected not to be tolerant for bovine proteins.
• Patients who are, in the opinion of the investigator, unsuitable for the study. A well-documented screening log should be present in the clinic.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: bIAP; intravenous as a bolus of bIAP (alkaline phosphatase, 1000 IU) just prior to surgery followed by a 40 IU/kg bIAP infusion during the first 8 hours post surgery.	Drug: bIAP bolus and 8h infusion; intravenous as a bolus of bIAP (bovine intestinal alkaline phosphatase, 1000 IU) just prior to surgery followed by a 40 IU/kg bIAP infusion during the first 8 hours post surgery.
PLACEBO_COMPARATOR: placebo; intravenous as a bolus just prior to surgery followed by an infusion during the first 8 hours post surgery.	Drug: placebo bolus and 8h infusion; intravenous as a bolus just prior to surgery followed by an infusion during the first 8 hours post surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TNF-alpha	as indicator of post-surgical inflammatory response	one day before till 5 days post surgery

Secondary Outcome Measures

Outcome Measure	Time Frame
incidence of new organ dysfunctions	till 30 days post surgery

Collaborators and Investigators

• Sponsor: Alloksys Life Sciences B.V.
• Collaborators: Aix Scientifics
• Investigators: Principal Investigator: M.Erwin S.H. Tan, Prof.Dr.med., Catharina Ziekenhuis, Dept. CardioThoracic Surgery

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ACTUAL): December 1, 2013
• Study Completion (ACTUAL): December 1, 2013

Study Registration Dates

• First Submitted: June 14, 2010
• First Submitted That Met QC Criteria: June 14, 2010
• First Posted (ESTIMATE): June 15, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): September 20, 2016
• Last Update Submitted That Met QC Criteria: September 19, 2016
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: CABG; valve replacement; SIRTS; Combined aortic valve replacement and CABG surgery
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: ALS-002-2009; 2009-010191-19 (EUDRACT_NUMBER)