Bovine Intestinal Alkaline Phosphatase for the Treatment of Patients With Sepsis
Condition: Sepsis; Multiple Organ Dysfunction Syndrome
MeSH terms: Sepsis; Toxemia; Multiple Organ Failure
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): Alkaline Phosphatase; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Intravenous over a period of 24 hours; Saline over a period of 24h
Other intervention name(s): AP, BIAP, CIAP; saline
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Sepsis; Alkaline; Phosphatase; Lipopolysaccharide