Ulcerative ColitisPhase 2NCT00727324
Safety/Efficacy Study of Bovine Intestinal Alkaline Phosphatase in Patients With Moderate to Severe Ulcerative Colitis
A Phase 2 study testing bovine intestinal alkaline phosphatase (BIAP) in people with Ulcerative Colitis, run by AM-Pharma at 11 sites in 2 countries.
Trial summary
Ulcerative colitis is characterized by abnormal activation of, and damage to, the colon epithelium, which is considered to be a central pathogenic mechanism. Activation of colon epithelium cells in UC is associated with an abnormal high expression of Toll-like receptors, including TLR-4, the major transducer of LPS… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Ulcerative Colitis
- What is being tested?
- bovine intestinal alkaline phosphatase (BIAP)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 11 sitesin 2 countries
- Study dates
- May 2006to Dec 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age, >18 years, AND
- Capable of understanding the purpose and risks of the study and have provided a signed and dated written IC, AND
- Prior to the study baseline, been treated with oral steroid medication, of which > 2 weeks on oral prednisone equivalent of at least 40mg/day, and still have:
- active ulcerative colon disease documented by a MAYO score of 6-11, and
- active ulcerative colon disease documented by a MTWSI score of 7-15
- OR
Show all 13Show fewer
- Prior to the study baseline, documented clinical inability to decrease or stop the course of oral steroid medication. Subjects have been treated for a minimum of 12 weeks, and still have:
- chronic active ulcerative colon disease documented by a MAYO score of 6-11, and
- chronic active ulcerative colon disease documented by a MTWSI score of 7-15
- OR
- Prior to the study baseline, been treated with a stable dosage of azathioprine for a minimum of 12 weeks, and have a moderate to severe relapse defined as:
- chronic active ulcerative colon disease documented by a MAYO score of 6-11, and
- chronic active ulcerative colon disease documented by a MTWSI score of 7-15.
Who cannot join
- UC, requiring immediate surgical, endoscopic, or radiological intervention; including massive haemorrhage, perforation and sepsis, suppurative complications (intra-abdominal or peri-anal abscesses) or toxic colon,
- history of large bowel surgery,
- history of serious infections,
- positive stool cultures, including Clostridium difficile,
- significant organ dysfunction,
- pregnancy, nursing mothers, or women of childbearing potential without appropriate use of contraceptives,
Show all 11Show fewer
- treatment with:
- an altered dose of any 5-ASA preparation within 4 weeks of screening,
- an altered dose of azathioprine or mercaptopurine within 4 weeks of screening (stable dosage of immunosuppressives is allowed), or start of azathioprine in the last 3 months prior to baseline,
- probiotics, antibiotics within 1 month, methotrexate or cyclosporine within 2 months prior to screening,
- any experimental treatment for this population e.g. infliximab, tacrolimus, FK506 or other anti TNFα therapy) within 2 months of screening.
Trial locations and contacts
11 sites in 2 countries.
11 sites in 2 countries
Italy7 sites
Università di Ancona - Nuovo Complesso Didattico, Facoltà di Medicina e Chirurgia, Clinica di Gastroenterologia
Ancona, Torrette, 60020
University of Bologna, Dept of Internal Medicine and Gastroenterology
Bologna, I-40138
Ospedale di Marsciano, Ambulatorio Gastroenterologia
Marsciano, 06055
Ospedale Santa Maria delle Croci, Servizio di Gastroenterologia e Endoscopia Digestiva
Ravenna, 48100
Università Cattolica di Roma, Dipartimento di Medicina Interna
Roma, 00168
Azienda Ospedaliera S. Camillo - Forlanini
Roma, I-00152
Ospedale Mauriziano, UOA Gastroenterologia
Torino, 10128
Czechia4 sites
Teaching Hospital Olomouc, Dep. Internal Clinic
Olomouc, 775 20
Internal Clinic, Vitkovice Hospital Ostrava
Ostrava, Vitkovice, 703 84
Center of Gastroenterology at General Teaching Hospital
Prague, 120 00
Institute of Clinical and Preventive Medicine (IKEM), Clinic of Hepatogastroenterology
Prague, 40 21
About this study
Official title: A Pilot, Open-label, Multi-center Clinical Trial to Investigate the Safety and Efficacy of Bovine-Calf Intestinal Alkaline Phosphatase in Patients With Moderate to Severe Ulcerative Colitis.
Ulcerative colitis is characterized by abnormal activation of, and damage to, the colon epithelium, which is considered to be a central pathogenic mechanism. Activation of colon epithelium cells in UC is associated with an abnormal high expression of Toll-like receptors, including TLR-4, the major transducer of LPS, binding specifically the lipid A portion of LPS. Alkaline Phosphatase binds and subsequently dephosphorylates LPS, thereby eliminating the ability of LPS to activate TLR-4. This is expected to 1) prevent activation of the intestinal epithelium and 2) prevent systemic inflammatory responses that result from transmigration of endotoxin though the leaky inflamed intestinal mucosa. Therefore, it is expected that administration of BIAP may attenuate or prevent the local and systemic inflammatory response in patients with severe ulcerative colitis.
Read the detailed description
Inflammatory Bowel Disease (IBD) is a general term for a group of non-specific, chronic inflammatory disorders of the digestive tract, of unknown etiology. IBD may be divided in two major categories: Ulcerative colitis and Crohn's disease, both characterized by a tendency towards frequent acute relapses leading to devastating chronic destruction of the intestinal mucosal barrier function. Whereas Crohn's disease can affect the whole digestive tract, ulcerative colitis is characterized by colonic involvement only. Surgical intervention is frequently required in both Crohn's disease and ulcerative colitis. Therapeutic intervention to date predominantly is based on reduction of induced local mucosal- or systemic inflammation by the use of 5-ASA, corticosteroids, cyclosporine, or TNFα antibodies.
In IBD, the delicate balance between pro-inflammatory molecules, anti-inflammatory molecules and immunoregulatory cells, which tightly regulate the immune system, is disrupted and this results in chronic, relapsing inflammation. Tissue and plasma concentrations of pro-inflammatory cytokines such as IFN-gamma, IL-1ß, IL-6, IL-8 and TNFα are elevated in inflammatory bowel disease and correlate with IBD activity.
In patients with inflammatory bowel diseases circulating LPS have been detected and also increased AP levels have been observed. The presence of the endotoxin is probably the consequence of the damaged intestinal mucosa leading to an increased LPS influx or gut translocation and causing or aggravating the systemic inflammatory response. The increased AP levels observed in these patients may be caused by the suboptimal detoxification of the gut-derived influx of LPS and a response thereof of non-intestinal organs. Thus it has been proposed that the liver sheds alkaline phosphatase (fast acting liver alkaline phosphatase) massively after having been insulted with LPS.
Systemic consequences of IBD may be induced and/or aggravated significantly by the influx of LPS. The proposed normal natural defense mechanism against LPS does include, amongst others, the cleavage of one of the phosphate groups from LPS by endogenous AP. It is therefore conceivable that a reduction in the amount of active LPS in the intestinal lumen by exogenously administered AP will result in a corresponding relative decrease of LPS-influx in the circulation of a subject and, as a consequence, inhibit the LPS medicated systemic inflammatory response. Moreover, dephosphorylated LPS will reduce the ability of LPS to activate TLR-4, resulting in decreased nuclear factor κB activation and a decreased local inflammatory response.
In order to investigate the clinical potential of exogenously administered BIAP for human use, its safety, tolerability and pharmacokinetics have previously been studied in animal toxicology studies and in subsequent Phase I and IIa clinical trials, respectively. These studies were done with intravenously administered BIAP. Following these studies and the successful completion of animal pharmacology studies and a human volunteer study with oral AP the next phase in the development of exogenously administered oral AP is to test the compound in a limited population of patients with IBD.
- Conditions
- Ulcerative Colitis
- Being tested
- bovine intestinal alkaline phosphatase (BIAP)
- Keywords
- Ulcerative Colitis, UC, moderate, severe, LPS, Alkaline Phosphatase, AP, BIAP, Mucositis
- Medical subject headings
- Colitis, Ulcerative, Lymphoma, Follicular, Mucositis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
bovine intestinal alkaline phosphatase (BIAP)Drug
Also called BIAP, AP
30,000U/24h for 7 consecutive days via a duodenal catheter
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | BIAP Receives: Drug: bovine intestinal alkaline phosphatase (BIAP) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Investigate the safety and tolerability of 7 days of BIAP administration in subjects with moderate to severe ulcerative colitis
Measured: 28 days
Secondary outcomes (2)
To evaluate the efficacy of 7 days of BIAP administration in subjects with moderate to severe ulcerative colitis
Measured: 63 days (9 weeks)
To evaluate the efficacy of 7 days of BIAP administration on related variables in subjects with moderate to severe ulcerative colitis
Measured: 63 days (9 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2008 (estimated)
- Study startMay 2006
- Primary completionNov 2006
- Study completionDec 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Ulcerative ColitisStudies 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- AM-Pharma
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- CRM Biometrics GmbH, Sintesi Research Srl, Vigilex BV
- Investigators
- Prof Milan Lukas, PhD, MD, Principal investigator, University Prague, Czech RepublicProf Paolo Gionchetti, PhD, MD, Principal investigator, Policlinico S. Orsola, Bologna, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00727324
- Sponsor's protocol ID
- AP IBD 02-02
- Status last verified
- Mar 2012
- First submitted
- 30 Jul 2008
- Last updated
- 2 Apr 2012
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Poelstra K, Bakker WW, Klok PA, Kamps JA, Hardonk MJ, Meijer DK. Dephosphorylation of endotoxin by alkaline phosphatase in vivo. Am J Pathol. 1997 Oct;151(4):1163-9.
PubMed 9327750Nakamura M, Saito H, Kasanuki J, Tamura Y, Yoshida S. Cytokine production in patients with inflammatory bowel disease. Gut. 1992 Jul;33(7):933-7. doi: 10.1136/gut.33.7.933.
PubMed 1644332Brynskov J, Nielsen OH, Ahnfelt-Ronne I, Bendtzen K. Cytokines (immunoinflammatory hormones) and their natural regulation in inflammatory bowel disease (Crohn's disease and ulcerative colitis): a review. Dig Dis. 1994 Sep-Oct;12(5):290-304. doi: 10.1159/000171464.
PubMed 7882549Lukas M, Drastich P, Konecny M, Gionchetti P, Urban O, Cantoni F, Bortlik M, Duricova D, Bulitta M. Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis. Inflamm Bowel Dis. 2010 Jul;16(7):1180-6. doi: 10.1002/ibd.21161.
PubMed 19885903
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, Open-label, Multi-center Clinical Trial to Investigate the Safety and Efficacy of Bovine-Calf Intestinal Alkaline Phosphatase in Patients With Moderate to Severe Ulcerative Colitis.
- ClinicalTrials.gov ID
- NCT00727324
- Acronym / sponsor ID
- AP IBD 02-02
- Conditions
- Ulcerative Colitis
- Keywords
- Ulcerative Colitis, UC, moderate, severe, LPS, Alkaline Phosphatase, AP, BIAP
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- AM-PharmaIndustry (pharma, biotech, devices)
- Collaborators
- CRM Biometrics GmbH, Sintesi Research Srl, Vigilex BV
- Study start
- May 2006
- Primary completion
- Nov 2006 (actual)
- Study completion
- Dec 2006 (actual)
- First posted
- 1 Aug 2008 (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.
Ulcerative colitis is characterized by abnormal activation of, and damage to, the colon epithelium, which is considered to be a central pathogenic mechanism. Activation of colon epithelium cells in UC is associated with an abnormal high expression of Toll-like receptors, including TLR-4, the major transducer of LPS, binding specifically the lipid A portion of LPS. Alkaline Phosphatase binds and subsequently dephosphorylates LPS, thereby eliminating the ability of LPS to activate TLR-4. This is expected to 1) prevent activation of the intestinal epithelium and 2) prevent systemic inflammatory responses that result from transmigration of endotoxin though the leaky inflamed intestinal mucosa. Therefore, it is expected that administration of BIAP may attenuate or prevent the local and systemic inflammatory response in patients with severe ulcerative colitis.
Detailed description
Inflammatory Bowel Disease (IBD) is a general term for a group of non-specific, chronic inflammatory disorders of the digestive tract, of unknown etiology. IBD may be divided in two major categories: Ulcerative colitis and Crohn's disease, both characterized by a tendency towards frequent acute relapses leading to devastating chronic destruction of the intestinal mucosal barrier function. Whereas Crohn's disease can affect the whole digestive tract, ulcerative colitis is characterized by colonic involvement only. Surgical intervention is frequently required in both Crohn's disease and ulcerative colitis. Therapeutic intervention to date predominantly is based on reduction of induced local mucosal- or systemic inflammation by the use of 5-ASA, corticosteroids, cyclosporine, or TNFα antibodies.
In IBD, the delicate balance between pro-inflammatory molecules, anti-inflammatory molecules and immunoregulatory cells, which tightly regulate the immune system, is disrupted and this results in chronic, relapsing inflammation. Tissue and plasma concentrations of pro-inflammatory cytokines such as IFN-gamma, IL-1ß, IL-6, IL-8 and TNFα are elevated in inflammatory bowel disease and correlate with IBD activity.
In patients with inflammatory bowel diseases circulating LPS have been detected and also increased AP levels have been observed. The presence of the endotoxin is probably the consequence of the damaged intestinal mucosa leading to an increased LPS influx or gut translocation and causing or aggravating the systemic inflammatory response. The increased AP levels observed in these patients may be caused by the suboptimal detoxification of the gut-derived influx of LPS and a response thereof of non-intestinal organs. Thus it has been proposed that the liver sheds alkaline phosphatase (fast acting liver alkaline phosphatase) massively after having been insulted with LPS.
Systemic consequences of IBD may be induced and/or aggravated significantly by the influx of LPS. The proposed normal natural defense mechanism against LPS does include, amongst others, the cleavage of one of the phosphate groups from LPS by endogenous AP. It is therefore conceivable that a reduction in the amount of active LPS in the intestinal lumen by exogenously administered AP will result in a corresponding relative decrease of LPS-influx in the circulation of a subject and, as a consequence, inhibit the LPS medicated systemic inflammatory response. Moreover, dephosphorylated LPS will reduce the ability of LPS to activate TLR-4, resulting in decreased nuclear factor κB activation and a decreased local inflammatory response.
In order to investigate the clinical potential of exogenously administered BIAP for human use, its safety, tolerability and pharmacokinetics have previously been studied in animal toxicology studies and in subsequent Phase I and IIa clinical trials, respectively. These studies were done with intravenously administered BIAP. Following these studies and the successful completion of animal pharmacology studies and a human volunteer study with oral AP the next phase in the development of exogenously administered oral AP is to test the compound in a limited population of patients with IBD.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: bovine intestinal alkaline phosphatase (BIAP)BIAP |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Age, >18 years, AND
- Capable of understanding the purpose and risks of the study and have provided a signed and dated written IC, AND
- Prior to the study baseline, been treated with oral steroid medication, of which > 2 weeks on oral prednisone equivalent of at least 40mg/day, and still have:
- OR
- Prior to the study baseline, documented clinical inability to decrease or stop the course of oral steroid medication. Subjects have been treated for a minimum of 12 weeks, and still have:
Key exclusion criteria (11 listed)
- UC, requiring immediate surgical, endoscopic, or radiological intervention; including massive haemorrhage, perforation and sepsis, suppurative complications (intra-abdominal or peri-anal abscesses) or toxic colon,
- history of large bowel surgery,
- history of serious infections,
- positive stool cultures, including Clostridium difficile,
- significant organ dysfunction,
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 |
|---|---|---|
| bovine intestinal alkaline phosphatase (BIAP)Also: BIAP, AP30,000U/24h for 7 consecutive days via a duodenal catheter | Drug | 1 |
Primary outcome
Investigate the safety and tolerability of 7 days of BIAP administration in subjects with moderate to severe ulcerative colitis
Time frame: 28 days
2 secondary outcomes
To evaluate the efficacy of 7 days of BIAP administration in subjects with moderate to severe ulcerative colitis
Time frame: 63 days (9 weeks)
To evaluate the efficacy of 7 days of BIAP administration on related variables in subjects with moderate to severe ulcerative colitis
Time frame: 63 days (9 weeks)
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 9327750Poelstra K, Bakker WW, Klok PA, Kamps JA, Hardonk MJ, Meijer DK. Dephosphorylation of endotoxin by alkaline phosphatase in vivo. Am J Pathol. 1997 Oct;151(4):1163-9.
- Background: PubMed 1644332Nakamura M, Saito H, Kasanuki J, Tamura Y, Yoshida S. Cytokine production in patients with inflammatory bowel disease. Gut. 1992 Jul;33(7):933-7. doi: 10.1136/gut.33.7.933.
- Background: PubMed 7882549Brynskov J, Nielsen OH, Ahnfelt-Ronne I, Bendtzen K. Cytokines (immunoinflammatory hormones) and their natural regulation in inflammatory bowel disease (Crohn's disease and ulcerative colitis): a review. Dig Dis. 1994 Sep-Oct;12(5):290-304. doi: 10.1159/000171464.
- Results publication: PubMed 19885903Lukas M, Drastich P, Konecny M, Gionchetti P, Urban O, Cantoni F, Bortlik M, Duricova D, Bulitta M. Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis. Inflamm Bowel Dis. 2010 Jul;16(7):1180-6. doi: 10.1002/ibd.21161.
- AM-Pharma HomepageLink provided by the sponsor.
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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.
Prof Milan Lukas, PhD, MD principal investigator
University Prague, Czech Republic
Prof Paolo Gionchetti, PhD, MD principal investigator
Policlinico S. Orsola, Bologna, Italy
11 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 bovine intestinal alkaline phosphatase (BIAP) in people with Ulcerative Colitis, run by AM-Pharma at 11 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 13 inclusion and 11 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 11 sites in Italy, Czechia. 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. 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?
Investigate the safety and tolerability of 7 days of BIAP administration in subjects with moderate to severe ulcerative colitis (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 NCT00727324, which also lists 4 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.