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Sponsored by: |
AM-Pharma |
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Information provided by: | AM-Pharma |
ClinicalTrials.gov Identifier: | NCT00430859 |
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 |
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Sepsis Multiple Organ Dysfunction Syndrome |
Drug: Alkaline Phosphatase Drug: Placebo |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Caregiver, Investigator), Placebo Control, Single Group Assignment, Safety/Efficacy Study |
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 |
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 |
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1: Experimental
BIAP
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Drug: Alkaline Phosphatase
Intravenous over a period of 24 hours
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Placebo: Placebo Comparator
Placebo, saline
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Drug: Placebo
Saline over a period of 24h
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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.
Ages Eligible for Study: | 18 Years to 80 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Belgium | |
University Hospital Antwerpen | |
Antwerpen, Belgium, B-2650 | |
Hospital Network Antwerpen - Middelheim | |
Antwerpen, Belgium, B-2020 | |
Belgium, Brussels Hoofdstedelijk Gewest | |
University Hospital Vrije Universiteit Brussel | |
Brussel, Brussels Hoofdstedelijk Gewest, Belgium, B-1090 | |
Netherlands | |
University Medical Centre Groningen | |
Groningen, Netherlands, 9700 RB | |
University Medical Centre Utrecht | |
Utrecht, Netherlands, 3508 GA | |
Netherlands, Friesland | |
Medical Centre Leeuwarden | |
Leeuwarden, Friesland, Netherlands, 8934 AD | |
Netherlands, Gelderland | |
University Medical Centre St. Radboud | |
Nijmegen, Gelderland, Netherlands, 6500 HB | |
Netherlands, N-Brabant | |
St. Elisabeth Hospital | |
Tilburg, N-Brabant, Netherlands, 5022 GC | |
Netherlands, Overijssel | |
Isala Clinics | |
Zwolle, Overijssel, Netherlands, 8011 JW | |
Netherlands, Z-Holland | |
Erasmus Medical Centre | |
Rotterdam, Z-Holland, Netherlands, 3015 GD |
Study Chair: | Bart Wuurman, M.Sc. | Unaffiliated |
Principal Investigator: | Hans JG van der Hoeven, MD, PhD | University Medical Centre St. Radboud |
Responsible Party: | AM-Pharma ( Dr J Arend, MD ) |
Study ID Numbers: | AP SEP 02-01, EudraCT No. 2005-005257-21 |
Study First Received: | February 1, 2007 |
Last Updated: | October 16, 2008 |
ClinicalTrials.gov Identifier: | NCT00430859 History of Changes |
Health Authority: | Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) |
Sepsis Alkaline Phosphatase Lipopolysaccharide |
Systemic Inflammatory Response Syndrome Sepsis Shock Multiple Organ Failure Inflammation |
Systemic Inflammatory Response Syndrome Sepsis Disease Pathologic Processes Shock |
Syndrome Multiple Organ Failure Infection Inflammation |