Bovine Intestinal Alkaline Phosphatase for the Treatment of Patients With Sepsis

Sepsis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00430859
• Other study ID #: AP SEP 02-01
• Secondary ID: EudraCT No. 2005
• Status: Completed
• Phase: Phase 2
• First received: February 1, 2007
• Last updated: March 30, 2012
• Start date: September 2004
• Est. completion date: March 2006

Study information

• Verified date: March 2012
• Source: AM-Pharma
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: March 2006
• Est. primary completion date: March 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Organ Dysfunction Syndrome
• Multiple Organ Failure
• Sepsis
• Toxemia

Intervention

Drug:
• Alkaline Phosphatase
Intravenous over a period of 24 hours
• Placebo
Saline over a period of 24h

Locations

Country	Name	City	State
Belgium	Hospital Network Antwerpen - Middelheim	Antwerpen
Belgium	University Hospital Antwerpen	Antwerpen
Belgium	University Hospital Vrije Universiteit Brussel	Brussel	Brussels Hoofdstedelijk Gewest
Netherlands	University Medical Centre Groningen	Groningen
Netherlands	Medical Centre Leeuwarden	Leeuwarden	Friesland
Netherlands	University Medical Centre St. Radboud	Nijmegen	Gelderland
Netherlands	Erasmus Medical Centre	Rotterdam	Z-Holland
Netherlands	St. Elisabeth Hospital	Tilburg	N-Brabant
Netherlands	University Medical Centre Utrecht	Utrecht
Netherlands	Isala Clinics	Zwolle	Overijssel

Sponsors (1)

Lead Sponsor	Collaborator
AM-Pharma

Countries where clinical trial is conducted

Belgium,  Netherlands, 

References & Publications (10)

Angus DC, Birmingham MC, Balk RA, Scannon PJ, Collins D, Kruse JA, Graham DR, Dedhia HV, Homann S, MacIntyre N. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA. 2000 Apr 5;283(13):1723-30. — View Citation

Annane D, Sébille V, Troché G, Raphaël JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000 Feb 23;283(8):1038-45. — View Citation

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. Review. — View Citation

Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997 Jul;112(1):235-43. Review. — View Citation

From the Centers for Disease Control. Increase in National Hospital Discharge Survey rates for septicemia--United States, 1979-1987. JAMA. 1990 Feb 16;263(7):937-8. — View Citation

Heemskerk S, Masereeuw R, Moesker O, Bouw MP, van der Hoeven JG, Peters WH, Russel FG, Pickkers P; APSEP Study Group. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med. 2009 Feb;37(2):417-23, e — View Citation

Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003 Apr 17;348(16):1546-54. — View Citation

Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227-42. Review. — View Citation

Pickkers P, Snellen F, Rogiers P, Bakker J, Jorens P, Meulenbelt J, Spapen H, Tulleken JE, Lins R, Ramael S, Bulitta M, van der Hoeven JG. Clinical pharmacology of exogenously administered alkaline phosphatase. Eur J Clin Pharmacol. 2009 Apr;65(4):393-402 — View Citation

Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995 Jan 11;273(2):117-23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	Clinical assessment after 90 days		90 days	Yes