Clinical trial NCT00583076: Safety and Efficacy of AST-120 in the Treatment of Pouchitis
Official title: A Pilot Study of the Safety and Efficacy of AST-120 in the Treatment of Active Pouchitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pouchitis
Keywords: Pouchitis
Active Pouchitis
Safety and Efficacy of AST120
Lead sponsor: Ocera Therapeutics
Sponsor class: INDUSTRY
First posted: 2007-12-31
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of the study is to assess the safety and efficacy of an investigational agent, AST-120, in treating patients with active pouchitis. This is an open-label trial which means that all patients will receive AST-120 in 2g sachets (packets)three times a day for 4 weeks. All antibiotics, probiotics and nutritional agents must have been discontinued for at least 2 weeks prior to study entry. An initial group of 10 patients will be enrolled. If there are no serious adverse events associated with the study drug and at least 3 of the 10 patients respond, a second group of 10 patients will be enrolled. In the second group of patients, those patients who are considered responders or who are in remission are eligible to receive open-label AST-120 for as long as response is maintained up to a maximum of 52 weeks. Patients will have clinic visits at the start of the study and at week 4. If continuing on open label AST-120 after week 4, patients will have clinic visits every 12 weeks to assess the continuing safety and efficacy of AST-120. Endoscopies will be performed at the start of the study, week 4, week 28, week 52 or early termination.

Detailed description: The management and prognosis vary in different types of pouchitis. For antibiotic-responsive pouchitis, the first-line therapy includes a 2-week course of metronidazole or ciprofloxacin. A relapsing course of pouchitis is common. Of the patients with acute pouchitis, 61% would develop at least one recurrence. Typically, patient's symptoms and endoscopic and histologic inflammation respond favorably to antibiotic therapy, but symptoms quickly recur when antibiotics are discontinued. This group of patients is classified as having antibiotic-dependent pouchitis and often requires long-term antibiotic or probiotic therapy to keep the disease in remission.

Although the majority of patients with active pouchitis respond favorably to antibiotic therapy, relapse is common, which often requires frequent antibiotic therapy. The concerns about frequent use of antibiotic agents are: 1)antibiotics such as metronidazole often cause adverse effects; 2)long-term or frequent use of antibiotics, including ciprofloxacin, metronidazole, and rifaximin, often leads to bacterial resistance. In clinical practice, we have encountered more and more patients with antibiotic-refractory pouchitis, which could largely be due to overuse of antibiotic agents; 3)UC patients with IPAA have an increased risk for the development of intra-abdominal infections, such as pouch leaks, abscess, and cholangitis from primary sclerosing cholangitis, which require antibiotic therapy with agents similar to the agents used in pouchitis. Bacterial resistance developed from the overuse of antibiotics for pouchitis might jeopardize the treatment of other intra-abdominal infections; 4) overuse of antibiotics can lead to overload of certain commensal bacteria or pathogenic bacteria, leading to pouch inflammation. Therefore, safe and effective agents are needed to treat active pouchitis, particularly on a long-term basis.

AST-120 is manufactured by Kureha Corporation, Japan. The agent was approved in Japan in 1992 for the treatment of patients with chronic kidney disease (CKD). It is comprised of highly adsorptive, porous, spherical carbon particles and is packaged in 2 g sachets for oral administration designed for the treatment of gastrointestinal diseases. AST-120 consists of black microspheres approximately 0.2-0.4 mm in diameter with high adsorption ability and large surface area. Composed mainly of carbon (approximately 96%), the clinical utility of AST-120 is thought to reside in its ability to adsorb low molecular weight toxins, inflammatory mediators, and harmful bile acid products from the gastrointestinal tract, preventing local toxicity and their systemic absorption. AST-120 has a selective adsorption profile for certain acidic and basic organic compounds, and has a significantly lower adsorptive capacity than activated charcoal for digestive enzymes.

This study is an open-label pilot trial in which all patients will receive AST-120 in 2 g sachets three times a day (to be taken between meals at 10:00 am, 3:00 pm, and immediately before going to bed) for 4 complete weeks. AST-120 is a tasteless, odorless, oral preparation. To take the product, patients will tear open the sachets, drop the contents directly on their tongue and wash it down with 8 ounces of water. All antibiotics, probiotics and nutritional agents must have been discontinued for at least 2 weeks prior to study entry. For purposes of this trial response is defined as a \> or = 3 point reduction in the 18-point PDAI scoring system. Remission is defined as a PDAI score \< 7.

The study population will consist of patients with active pouchitis after ileal pouch-anal anastomosis for Ulcerative Colitis (UC) present with primary symptoms such as increased stool frequency and abdominal pain. The diagnosis of active pouchitis will be defined by a PDAI score \> 7 points, with a combined assessment of symptoms, endoscopy, and histology.

An initial cohort of 10 patients will be enrolled. Based on the efficacy outcome (at least 3 out of 10 patients responding) and safety outcome (no significant adverse event associated with study drug) a second cohort of 10 patients will be treated. Patients in the second cohort who are considered responders (i.e., have had at least a 3 point reduction in the 18 point PDAI scoring system) or who are in remission (PDAI\<7) are eligible to receive open-label AST-120 for as long as response is maintained up to a maximum of 52 weeks. If, at any time, the patient relapses (PDAI\>7 for patients who were in remission, or an increase in PDAI such that at least a 3 point reduction is not maintained for responders), open-label treatment will be discontinued and the patient will be removed from the study. Patients will also discontinue open-label treatment and be removed from the study if warranted by treatment-emergent safety concerns or if, in the opinion of the investigator, it is in the patient's best interest to discontinue the study.

Eligibility criteria: Inclusion Criteria:

* Patients with a current episode of active pouchitis (defined as having a PDAI score \> 7) after IPAA for UC confirmed by endoscopy and histology
* Patients with active pouchitis who have never been treated with antibiotics (antibiotic-naive) or who have been previously treated with antibiotics and responded. Antibiotic-dependent patients may be enrolled as long as antibiotic use is discontinued for at least two weeks prior to study entry. Antibiotic-dependent pouchitis is defined as a condition in which a patient with frequent episodes (\> or = 4 episodes per year) of pouchitis or persistent symptoms requires long-term, continuous antibiotic or probiotic therapy to keep the disease in remission.
* Able to give informed consent
* Able and willing to comply with all study procedures
* Females must be post-menopausal, surgically incapable of bearing children, or practicing a reliable single barrier method of birth control (condom, intrauterine devices, spermicide and barrier, Depot). Partner/spouse sterility may also qualify at the investigator's discretion. Females of child-bearing potential must have a negative urine pregnancy test at baseline. Oral contraceptives are not acceptable as there is a potential interaction with AST-120.

Exclusion Criteria:

* Patients previously treated with infliximab or any investigational immunosuppressant/immunomodulator
* Patients whose condition is severe enough that, in the investigator's opinion, withholding antibiotics for 4 weeks during the AST-120 trial is not feasible
* Patients undergoing chemotherapy for the treatment of cancer
* Antibiotic use within 2 weeks prior to the entry of the study
* Crohn's disease of the pouch, including inflammatory, fibrostenotic, or fistulizing phenotypes, based on the previously established diagnostic criteria (Shen B, et al. Am J Gastroenterol 2006 in press)
* Active specific infection of the pouch: cytomegalovirus infection and C. difficile infection
* Patients with chronic antibiotic-refractory pouchitis. Antibiotic- refractory pouchitis is defined as a condition where a patient fails to respond to a 4 week course of a single antibiotic (metronidazole or ciprofloxacin), requiring prolonged therapy of \> or = 4 weeks consisting of 2 antibiotics, oral or topical 5-aminosalicylate, corticosteroid therapy, or oral immunomodulator therapy.
* History of non-inflammatory disease of the pouch: decreased pouch compliance, irritable pouch syndrome, afferent or efferent limb obstruction
* Isolated cuffitis. Patients who have active pouchitis as the predominant condition, but also have cuffitis may be enrolled.
* Strictures of the pouch inlet or outlet
* Ileal pouch patients with familial adenomatous polyposis
* History of lactose intolerance
* Known celiac disease
* Primary sclerosing cholangitis (PSC) with or without liver transplant; PSC with or without Actigall or Urso therapy
* Uncontrolled systemic diseases
* Needing oral or topical steroid treatment or 5-ASA agents
* Other major physical or major psychiatric illness within the last 6 months that in the opinion of the investigator would affect the patient's ability to complete the trial
* Active use of cholestyramine
* Active use of NSAIDs or aspirin
* Women who are pregnant, breast feeding, or planning to become pregnant during the study
* Patients who are on therapy of 5-ASA at the entry of the study

Primary outcomes:
measure: Remission induction as defined by a Pouchitis Disease Activity Index (PDAI) score < 7 (Sandborn et al, Mayo Clin Proc 1994), as well as maintenance of remission over 12 months
timeFrame: 4 weeks induction, 12 months maintenance of remission
measure: Safety: Any adverse events (AEs) deemed possibly, probably, or definitely related to treatment with investigational product
timeFrame: 4 weeks induction, 12 months maintenance of remission
Secondary outcomes:
measure: Response defined as a > or = 3 point reduction in the 18-point PDAI scoring system
timeFrame: 4 weeks, weeks 28 and 52
measure: Reduction of PDAI clinical symptom score, range from 0 to 6 (e.g., stoll frequency returns to the normal baseline)
timeFrame: 4 weeks, weeks 28 and 52
measure: Reduction of PDAI endoscopic score, range from 0 to 6
timeFrame: 4 weeks, weeks 28 and 52
measure: Reduction of PDAI histology score, range from 0 to 6
timeFrame: 4 weeks, weeks 28 and 52
measure: Need for rescue medication or increased quantity of antidiarrheal medication used during the trial
timeFrame: 4 weeks, weeks 28 and 52
measure: Quality of Life (Cleveland Global Quality of Life [CGQL] and Short Inflammatory Bowel Disease Questionnaire [SIBDQ]
timeFrame: 4 weeks, through 52 weeks
measure: Clinical laboratory tests including liver transaminases and alkaline phosphatase
timeFrame: 4 weeks, through 52 weeks
measure: Worsening GI symptoms (diarrhea, abdominal pain, urgency or bleeding) or new GI and ex-intestinal systemic symptoms (such as headache, nausea, vomiting, and constipation)
timeFrame: 4 weeks, through 52 weeks
measure: Physical examination, vital signs (blood pressure, heart rate, respiration rate and temperature)
timeFrame: 4 weeks, through 52 weeks
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
affiliation: Clevland Clinic
name: Bo Shen, MD
role: PRINCIPAL_INVESTIGATOR
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