SepsisPhase 2NCT00430859
Bovine Intestinal Alkaline Phosphatase for the Treatment of Patients With Sepsis
A Phase 2 study testing Alkaline Phosphatase in people with Sepsis and Multiple Organ Dysfunction Syndrome, run by AM-Pharma at 10 sites in 2 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Sepsis, Multiple Organ Dysfunction Syndrome
- What is being tested?
- Alkaline Phosphatase
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 37 participants
- Where
- 10 sitesin 2 countries
- Study dates
- Sep 2004to Mar 2006
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
Show all 12Show fewer
- 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.
Trial locations and contacts
10 sites in 2 countries.
10 sites in 2 countries
Netherlands7 sites
University Medical Centre Groningen
Groningen, Provincie Groningen, 9700 RB
Medical Centre Leeuwarden
Leeuwarden, Provincie Friesland, 8934 AD
University Medical Centre St. Radboud
Nijmegen, Gelderland, 6500 HB
Erasmus Medical Centre
Rotterdam, Z-Holland, 3015 GD
St. Elisabeth Hospital
Tilburg, North Brabant, 5022 GC
University Medical Centre Utrecht
Utrecht, Utrecht, 3508 GA
Isala Clinics
Zwolle, Overijssel, 8011 JW
Belgium3 sites
Hospital Network Antwerpen - Middelheim
Antwerp, Antwerpen, B-2020
University Hospital Antwerpen
Antwerp, Antwerpen, B-2650
University Hospital Vrije Universiteit Brussel
Brussels, Brussels Capital, B-1090
About this 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
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.
Read the 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.
- Conditions
- Sepsis, Multiple Organ Dysfunction Syndrome
- Being tested
- Alkaline Phosphatase, Placebo
- Keywords
- Sepsis, Alkaline, Phosphatase, Lipopolysaccharide
- Medical subject headings
- Sepsis, Multiple Organ Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Alkaline PhosphataseDrug
Also called AP, BIAP, CIAP
Intravenous over a period of 24 hours
PlaceboDrug
Also called saline
Saline over a period of 24h
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | BIAP Receives: Drug: Alkaline Phosphatase |
| Placebo | Placebo comparator | Placebo, saline Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 28 days
Secondary outcomes (3)
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
Measured: 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.
Measured: 28
Clinical assessment after 90 days
Measured: 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2007 (estimated)
- Study startSep 2004
- Primary completionMar 2006
- Study completionMar 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind
- Who is masked
- Care provider, Investigator
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- AM-Pharma
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Bart Wuurman, M.Sc., Study chairHans JG van der Hoeven, MD, PhD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00430859
- Sponsor's protocol ID
- AP SEP 02-01
- Other IDs
- EudraCT No. 2005-005257-21
- Status last verified
- Mar 2012
- First submitted
- 1 Feb 2007
- Last updated
- 2 Apr 2012
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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. doi: 10.1056/NEJMoa022139.
PubMed 12700374Rangel-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.
PubMed 7799491From 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. No abstract available.
PubMed 2299753Angus 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. doi: 10.1001/jama.283.13.1723.
PubMed 10755499Annane D, Sebille V, Troche G, Raphael 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. doi: 10.1001/jama.283.8.1038.
PubMed 10697064Parrillo 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. doi: 10.7326/0003-4819-113-3-227.
PubMed 2197912Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997 Jul;112(1):235-43. doi: 10.1378/chest.112.1.235. No abstract available.
PubMed 9228382Bone 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. doi: 10.1378/chest.101.6.1644.
PubMed 1303622Heemskerk 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, e1. doi: 10.1097/CCM.0b013e31819598af.
PubMed 19114895Pickkers 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. doi: 10.1007/s00228-008-0591-6. Epub 2008 Dec 2.
PubMed 19048243
Study at a glance
From the registry record, last updated by the sponsor on 2 Apr 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00430859
- Acronym / sponsor ID
- AP SEP 02-01
- Conditions
- Sepsis, Multiple Organ Dysfunction Syndrome
- Keywords
- Sepsis, Alkaline, Phosphatase, Lipopolysaccharide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- AM-PharmaIndustry (pharma, biotech, devices)
- Study start
- Sep 2004
- Primary completion
- Mar 2006 (actual)
- Study completion
- Mar 2006 (actual)
- First posted
- 2 Feb 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind (care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Alkaline PhosphataseBIAP |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo, saline |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (12 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Alkaline PhosphataseAlso: AP, BIAP, CIAPIntravenous over a period of 24 hours | Drug | 1 |
| PlaceboAlso: salineSaline over a period of 24h | Drug | Placebo |
Primary outcome
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
3 secondary outcomes
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
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
Clinical assessment after 90 days
Time frame: 90 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Apr 2012.
- Background: PubMed 12700374Martin 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. doi: 10.1056/NEJMoa022139.
- Background: PubMed 7799491Rangel-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.
- Background: PubMed 2299753From 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. No abstract available.
- Background: PubMed 10755499Angus 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. doi: 10.1001/jama.283.13.1723.
- Background: PubMed 10697064Annane D, Sebille V, Troche G, Raphael 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. doi: 10.1001/jama.283.8.1038.
- Background: PubMed 2197912Parrillo 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. doi: 10.7326/0003-4819-113-3-227.
- Background: PubMed 9228382Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997 Jul;112(1):235-43. doi: 10.1378/chest.112.1.235. No abstract available.
- Background: PubMed 1303622Bone 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. doi: 10.1378/chest.101.6.1644.
- Results publication: PubMed 19114895Heemskerk 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, e1. doi: 10.1097/CCM.0b013e31819598af.
- Results publication: PubMed 19048243Pickkers 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. doi: 10.1007/s00228-008-0591-6. Epub 2008 Dec 2.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bart Wuurman, M.Sc. study chair
Hans JG van der Hoeven, MD, PhD principal investigator
Radboud University Medical Center
10 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Alkaline Phosphatase in people with Sepsis and Multiple Organ Dysfunction Syndrome, run by AM-Pharma at 10 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Apr 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00430859, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Apr 2012.