Bovine Intestinal Alkaline Phosphatase for the Treatment of Patients With Sepsis

Sponsor

AM-Pharma (Industry)

Overall Status

Completed

CT.gov ID

NCT00430859

Collaborator

(none)

Enrollment

Locations

Arms

17.9

Duration (Months)

3.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Sepsis Multiple Organ Dysfunction Syndrome	Drug: Alkaline Phosphatase Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

37 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Double (Care Provider, 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

Study Start Date :

Sep 1, 2004

Actual Primary Completion Date :

Mar 1, 2006

Actual Study Completion Date :

Mar 1, 2006

Arms and Interventions

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

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

Outcome Measures

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. [28 days]

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 [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. [28]
Clinical assessment after 90 days [90 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Vrije Universiteit Brussel	Brussel	Brussels Hoofdstedelijk Gewest	Belgium	B-1090
2	Hospital Network Antwerpen - Middelheim	Antwerpen		Belgium	B-2020
3	University Hospital Antwerpen	Antwerpen		Belgium	B-2650
4	Medical Centre Leeuwarden	Leeuwarden	Friesland	Netherlands	8934 AD
5	University Medical Centre St. Radboud	Nijmegen	Gelderland	Netherlands	6500 HB
6	St. Elisabeth Hospital	Tilburg	N-Brabant	Netherlands	5022 GC
7	Isala Clinics	Zwolle	Overijssel	Netherlands	8011 JW
8	Erasmus Medical Centre	Rotterdam	Z-Holland	Netherlands	3015 GD
9	University Medical Centre Groningen	Groningen		Netherlands	9700 RB
10	University Medical Centre Utrecht	Utrecht		Netherlands	3508 GA