Bovine Intestinal Alkaline Phosphatase for the Treatment of Patients With Sepsis

March 30, 2012 updated by: AM-Pharma

A Pilot, Double-blind, Randomised, Placebo-controlled, Exploratory Study to Investigate the Safety and Effect of Bovine Intestinal Alkaline Phosphatase in Patients With Sepsis

Eligible patients will receive either AP or matching placebo in a double blind, randomized design and following a 2:1 ratio. All medication will be given in addition to standard care for sepsis patients. Patients will be followed for 28 days after the start of study medication administration. A blinded safety review of the study results will take place after the inclusion of 12 patients in the study.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Both bolus and continuous infusions were found to effectively reduce the LPS-induced pro-inflammatory cytokine TNFα in piglets. When AP was administered as a bolus (160 U/kg), the reduction of TNFα after administration of 10 μg/kg LPS in piglets was found to be in the order of 32%. When 100 U/kg of CIAP was administered as an infusion over 50 minutes, reaching steady state levels of 400 U/L, the reduction in TNFα after LPS challenge was substantially (70%), as compared to TNFα levels after LPS only. A series of these studies demonstrated that dosages of 100-120 U/kg administered over 50 minutes could effectively reduce LPS toxicity at steady state levels around 400 U/L, about a 10 fold of the normal alkaline phosphatase plasma levels (40 U/L in piglets). Furthermore, it is estimated that the above-mentioned dosages can effectively detoxify 10 μg LPS/kg in piglets, which represents an LPS-equivalent derived from about 1010 colony forming units (cfu) of E.coli. These amounts of circulating bacteria are not easily established in a sepsis patient. It is estimated (personal communication, Prof. S. van Deventer, Academic Medical Centre, Amsterdam) that the bacterial load in these patients is less than 107 bacteria total, which is equivalent to approx. 2x105 cfu/kg.

In summary, in piglets 160 U/kg AP was able to detoxify an amount of LPS equivalent to 1010 cfu E. Coli/kg, which is approximately 50,000 times the expected amount of bacteria in sepsis patients. We therefore expect that the dosage used in human (200 U/kg) administered over 24 hours is able to detoxify the amount of LPS present in sepsis patients. This dosage will result in 5-times normal plasma level of alkaline phosphatase which was well tolerated during the previous clinical trials. Since the effect of antibiotic treatment is expected to occur within hours of administration we decided to establish this steady state level of AP as fast as possible, which explains the initial bolus-like administration by short infusion, followed by a prolonged steady state infusion.

Study Type

Interventional

Enrollment (Actual)

37

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Antwerpen, Belgium, B-2650
        • University Hospital Antwerpen
      • Antwerpen, Belgium, B-2020
        • Hospital Network Antwerpen - Middelheim
    • Brussels Hoofdstedelijk Gewest
      • Brussel, Brussels Hoofdstedelijk Gewest, Belgium, B-1090
        • University Hospital Vrije Universiteit Brussel
  • Netherlands
      • Groningen, Netherlands, 9700 RB
        • University Medical Centre Groningen
      • Utrecht, Netherlands, 3508 GA
        • University Medical Centre Utrecht
    • Friesland
      • Leeuwarden, Friesland, Netherlands, 8934 AD
        • Medical Centre Leeuwarden
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6500 HB
        • University Medical Centre St. Radboud
    • N-Brabant
      • Tilburg, N-Brabant, Netherlands, 5022 GC
        • St. Elisabeth Hospital
    • Overijssel
      • Zwolle, Overijssel, Netherlands, 8011 JW
        • Isala Clinics
    • Z-Holland
      • Rotterdam, Z-Holland, Netherlands, 3015 GD
        • Erasmus Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients between 18 and 80 years (inclusive);
  • proven or suspected infection;
  • meeting 2 of 4 of the systemic inflammatory response syndrome (SIRS) criteria;
  • septic shock or one or more acute organ failures in the preceding 12 hours;
  • written informed consent obtained.

Exclusion Criteria:

  • Pregnant or lactating women;
  • known HIV seropositive patients;
  • patients receiving immunosuppressive therapy or chronically using high doses of glucocorticosteroids (defined as > 1 mg/kg/day) equivalent to prednisone 1 mg/kg/day;
  • patients expected to have rapidly fatal disease within 24 h;
  • known confirmed gram-positive sepsis;
  • known confirmed fungal sepsis;
  • chronic renal failure requiring haemodialysis or peritoneal dialysis;
  • acute pancreatitis with no established source of infection;
  • patients not expected to survive for 28 days due to other medical conditions such as end-stage neoplasm or other diseases;
  • participation in another investigational study within 90 days prior to start of the study which might interfere with this study;
  • previous administration of AP;
  • known allergy for cow milk.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
BIAP
Drug: Alkaline Phosphatase
Intravenous over a period of 24 hours
Other Names:
  • AP, BIAP, CIAP
Placebo Comparator: Placebo
Placebo, saline
Drug: Placebo
Saline over a period of 24h
Other Names:
  • saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Presence of (Serious) Adverse Events ((S)AEs), vital signs (body temperature, heart rate), systolic and diastolic blood pressure, electrocardiogram variables, biochemical, haematological, and coagulation variables, and frequency and type of anti-AP.
Time Frame: 28 days
28 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Variables for evaluation of the effect on inflammation: C-reactive protein (CRP), plasma lactate, cytokines (TNFalfa, IL-6, IL-8, IL-10), white cell count, and procalcitonin (PCT) were assessed.differential
Time Frame: 28
28
Evaluation effect: APACHE-II score, overall mortality at 28 days, length of stay at ICU, number of days requiring mechanical ventilation, length of stay in hospital, SOFA score, and number of dysfunctional organs were assessed.
Time Frame: 28
28
Clinical assessment after 90 days
Time Frame: 90 days
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AM-Pharma

Investigators

  • Study Chair: Bart Wuurman, M.Sc.
  • Principal Investigator: Hans JG van der Hoeven, MD, PhD, Radboud University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2004

Primary Completion (Actual)

March 1, 2006

Study Completion (Actual)

March 1, 2006

Study Registration Dates

First Submitted

February 1, 2007

First Submitted That Met QC Criteria

February 1, 2007

First Posted (Estimate)

February 2, 2007

Study Record Updates

Last Update Posted (Estimate)

April 2, 2012

Last Update Submitted That Met QC Criteria

March 30, 2012

Last Verified

March 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AP SEP 02-01
  • EudraCT No. 2005-005257-21

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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