Bovine Intestinal Alkaline Phosphatase for the Treatment of Patients With Sepsis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AM-Pharma
ClinicalTrials.gov Identifier:
NCT00430859
First received: February 1, 2007
Last updated: March 30, 2012
Last verified: March 2012
  Purpose

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.


Condition Intervention Phase
Sepsis
Multiple Organ Dysfunction Syndrome
Drug: Alkaline Phosphatase
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Pilot, Double-blind, Randomised, Placebo-controlled, Exploratory Study to Investigate the Safety and Effect of Bovine Intestinal Alkaline Phosphatase in Patients With Sepsis

Resource links provided by NLM:


Further study details as provided by AM-Pharma:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Clinical assessment after 90 days [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]

Enrollment: 37
Study Start Date: September 2004
Study Completion Date: March 2006
Primary Completion Date: March 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
BIAP
Drug: Alkaline Phosphatase
Intravenous over a period of 24 hours
Other Name: AP, BIAP, CIAP
Placebo Comparator: Placebo
Placebo, saline
Drug: Placebo
Saline over a period of 24h
Other Name: saline

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00430859

Locations
Belgium
University Hospital Vrije Universiteit Brussel
Brussel, Brussels Hoofdstedelijk Gewest, Belgium, B-1090
University Hospital Antwerpen
Antwerpen, Belgium, B-2650
Hospital Network Antwerpen - Middelheim
Antwerpen, Belgium, B-2020
Netherlands
Medical Centre Leeuwarden
Leeuwarden, Friesland, Netherlands, 8934 AD
University Medical Centre St. Radboud
Nijmegen, Gelderland, Netherlands, 6500 HB
St. Elisabeth Hospital
Tilburg, N-Brabant, Netherlands, 5022 GC
Isala Clinics
Zwolle, Overijssel, Netherlands, 8011 JW
Erasmus Medical Centre
Rotterdam, Z-Holland, Netherlands, 3015 GD
University Medical Centre Groningen
Groningen, Netherlands, 9700 RB
University Medical Centre Utrecht
Utrecht, Netherlands, 3508 GA
Sponsors and Collaborators
AM-Pharma
Investigators
Study Chair: Bart Wuurman, M.Sc.
Principal Investigator: Hans JG van der Hoeven, MD, PhD Radboud University
  More Information

Publications:

Responsible Party: AM-Pharma
ClinicalTrials.gov Identifier: NCT00430859     History of Changes
Other Study ID Numbers: AP SEP 02-01, EudraCT No. 2005-005257-21
Study First Received: February 1, 2007
Last Updated: March 30, 2012
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by AM-Pharma:
Sepsis
Alkaline
Phosphatase
Lipopolysaccharide

Additional relevant MeSH terms:
Multiple Organ Failure
Sepsis
Toxemia
Shock
Pathologic Processes
Infection
Systemic Inflammatory Response Syndrome
Inflammation

ClinicalTrials.gov processed this record on April 17, 2014