Safety/Efficacy Study of Bovine 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.
Drug: bovine intestinal alkaline phosphatase (BIAP)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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.|
- Investigate the safety and tolerability of 7 days of BIAP administration in subjects with moderate to severe ulcerative colitis [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
- To evaluate the efficacy of 7 days of BIAP administration in subjects with moderate to severe ulcerative colitis [ Time Frame: 63 days (9 weeks) ] [ Designated as safety issue: No ]
- 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) ] [ Designated as safety issue: No ]
|Study Start Date:||May 2006|
|Study Completion Date:||December 2006|
|Primary Completion Date:||November 2006 (Final data collection date for primary outcome measure)|
Drug: bovine intestinal alkaline phosphatase (BIAP)
30,000U/24h for 7 consecutive days via a duodenal catheter
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.
|Internal Clinic, Vitkovice Hospital Ostrava|
|Ostrava, Vitkovice, Czech Republic, 703 84|
|Teaching Hospital Olomouc, Dep. Internal Clinic|
|Olomouc, Czech Republic, 775 20|
|Center of Gastroenterology at General Teaching Hospital|
|Prague, Czech Republic, 120 00|
|Institute of Clinical and Preventive Medicine (IKEM), Clinic of Hepatogastroenterology|
|Prague, Czech Republic, 40 21|
|Università di Ancona - Nuovo Complesso Didattico, Facoltà di Medicina e Chirurgia, Clinica di Gastroenterologia|
|Ancona, Torrette, Italy, 60020|
|University of Bologna, Dept of Internal Medicine and Gastroenterology|
|Bologna, Italy, I-40138|
|Ospedale di Marsciano, Ambulatorio Gastroenterologia|
|Marsciano, Italy, 06055|
|Ospedale Santa Maria delle Croci, Servizio di Gastroenterologia e Endoscopia Digestiva|
|Ravenna, Italy, 48100|
|Università Cattolica di Roma, Dipartimento di Medicina Interna|
|Roma, Italy, 00168|
|Azienda Ospedaliera S. Camillo - Forlanini|
|Roma, Italy, I-00152|
|Ospedale Mauriziano, UOA Gastroenterologia|
|Torino, Italy, 10128|
|Principal Investigator:||Prof Milan Lukas, PhD, MD||University Prague, Czech Republic|
|Principal Investigator:||Prof Paolo Gionchetti, PhD, MD||Policlinico S. Orsola, Bologna, Italy|