Safety and Efficacy of AST-120 in the Treatment of Pouchitis
Condition: Pouchitis
MeSH terms: Pouchitis
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): AST-120
Intervention type(s): Drug
Intervention description(s): AST-120, 2grams,three times daily for 4 weeks. Responders in the second cohort of patients are eligible to receive AST-120 for up to 52 weeks.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Pouchitis; Active Pouchitis; Safety and Efficacy of AST120