Clinical trial NCT00321412: Safety and Efficacy of AST-120 in Mild to Moderate Crohn's Patients With Fistulas
Official title: A Double-blind, Randomized, Placebo-controlled Multicenter Study to Assess the Safety and Efficacy of AST-120 in Mild to Moderately Active Crohn's Patients With Fistulas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Inflammatory Bowel Disease
Intestinal Fistula
Keywords: Crohn's disease
IBD
Inflammatory Bowel Disease
Fistula
Lead sponsor: Ocera Therapeutics
Sponsor class: INDUSTRY
First posted: 2006-05-03
Enrollment: 191
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to evaluate the safety and effectiveness of the experimental drug AST-120 in treating patients with mild to moderately severe Crohn's disease who have fistulas. The study will test whether or not patients receiving AST-120 experience a greater reduction in number of draining fistulas and improvement of their other Crohn's disease symptoms versus patients who receive placebo (material that does not contain any active medication).

Detailed description: The experimental drug AST-120 is composed of black, odorless spherical carbon particles in 2g sachets (aluminum foil pouches). The placebo consists of microcrystalline cellulose spheres, Celphere CP-305, stained to match the appearance of AST-120, in 2g sachets (aluminum foil pouches). Both AST-120 and placebo are oral (taken by mouth)preparations. Both are tasteless. 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.

Patients will be randomly assigned (like the toss of a coin), to receive either AST-120 or placebo. Patients will have a 50/50 chance of receiving placebo. Patients who participate in this study will be required to take a single dose of study drug (AST-120 or placebo) 3 times a day, 30 minutes after a meal, for 8 weeks, and be evaluated at Week 4 and Week 8. This is a 'blinded' treatment, which means that neither the patient nor the study doctor will know if the patient has received study drug or placebo.

If, at the end of the first full course of randomized treatment, (8 weeks), patients are not showing an improvement in their condition, they may have the option to receive the alternate blinded treatment for one treatment course (8 weeks). The study doctor will discuss this option with each patient individually. During this second course of treatment, patients will be evaluated at Week 12 and Week 16. If the patient does not respond to the alternate blinded treatment, or their condition worsens after 4 weeks (assessed at Week 12), they may be removed from the study at the discretion of the investigator.

If patients respond to either the initial treatment or the alternate blinded treatment, they will have monthly doctor/clinic visits for up to 6 months (Week 24), or until their condition worsens or they relapse. Patients will not receive any study drug during this follow-up period.

Relapse is defined for this study as:

* an increase by 1 or more in the number of draining fistulas for 2 sequential visits versus the number present at the time of response (response is defined as at least a 50% reduction in the number of draining fistulas at either Week 8, or for those patients receiving alternate blinded treatment, Week 16).

There are a maximum of 8 patient evaluation visits in this study (Screen, Baseline, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24). Evaluations at most of these visits include a review of concomitant medications, medical history/adverse events, physical exam, fistula exam, blood draws for safety labs, urine pregnancy tests for females, and measurement of body weight. Patients will also be asked to keep a daily diary to record frequency of bowel movements, general well-being, and use of antidiarrheal medication.

Treatment failure in this study is defined by one or more of the following occurring prior to Week 8:

* The need for additional therapies or dose increase for treatment of Crohn's disease, including an increase of corticosteroid dose to higher than baseline
* Clinical/symptomatic development of an abscess
* Clinical/symptomatic evidence of stricture
* The need for surgical intervention for Crohn's disease
* The patient withdraws from the study

Patients will be discontinued from the study at any time if one or more of the following complications occur:

* Development of an abscess or symptomatic stricture
* The need for surgical intervention for Crohn's disease
* Occurrence of any other event that in the opinion of the investigator warrants discontinuation of the patient from the study

In addition, patients whose CDAI score has risen by \> or = 70 points above baseline or risen above 400 will be discontinued from the study.

Administration of any additional therapies or dose increases of concomitant medications (including corticosteroids) to control Crohn's disease to higher than baseline while receiving study drug (initial randomized treatment or alternate blinded treatment) will require discontinuation of the patient from the study.

Discontinued patients will be evaluated in a termination visit to document the lack of treatment efficacy and no further study treatment will be given.

Eligibility criteria: Inclusion Criteria:

* Body Weight \> or = 40kg
* Documented diagnosis of Crohn's disease, including patients with documented diagnosis of ileitis, colitis, or ileocolitis
* Presence of at least one draining fistula. Patients with enterocutaneous fistulas can be included if they have \> or = 1 draining perianal fistula. Women with rectovaginal fistulas can be included if they have \> or = 1 draining perianal fistula.
* Crohn's Disease Activity Index (CDAI) score \< 400
* Platelet count (thrombocytes) \> or = 100,000/uL
* Able and willing to comply with all protocol procedures for the duration of the study
* Able and willing to understand, sign and date an informed consent document, and authorize access to protected health information
* Females must be postmenopausal, surgically incapable of bearing children, or practicing a reliable method of birth control (hormonal contraceptives, intrauterine devices, spermicide and barrier). 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.

Exclusion Criteria:

* Non-response to infliximab or other biological immunosuppressants/ immunomodulators for fistulas associated with Crohn's disease (response is defined as a \> or = 50% reduction from baseline in the number of fistulas over at least four weeks); patients who respond once to infliximab and eventually fail can be included
* Infliximab (and/or other biological immunosuppressant/immunomodulatory) therapy within 3 months prior to enrollment in the study
* Presence of symptomatic strictures or suggestion of significant clinical obstruction
* Patients with setons are excluded, unless the setons are removed within 48 hours prior to study entry
* Presence of entero-entero, recto-vesicular, entero-vesicular fistulas
* Platelet count (thrombocytes) \< 100,000/uL
* CDAI score of \> or = 400
* Patient is unable to stay on a stable dose of concomitant Crohn's disease medication(s) for at least 10 weeks in the opinion of the investigator
* Currently symptomatic untreated diarrhea due to conditions other than mild to moderately active Crohn's disease (e.g., bacterial or parasitic gastroenteritis, bile salt diarrhea, etc.)
* Severe diarrhea defined by \> 10 liquid bowel movements per day
* Other local manifestations of mild to moderately active Crohn's disease such as abscesses, or other disease manifestations for which surgery might be indicated or which might preclude utilization of a CDAI to assess response to therapy (e.g., short bowel syndrome)
* Presence of an ileostomy
* Receiving Total Parenteral Nutrition (TPN) as the sole source of nutrition within 3 weeks of Screen
* Poor tolerability of venipuncture or lack of adequate venous access for required blood sampling.
* Hemoglobin \< 8.5 g/dL (females) or hemoglobin \< 10 g/dL (males) at Screen
* Women who are pregnant, breast feeding, or planning to become pregnant during the study
* 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
* Uncontrolled systemic disease
* Patients undergoing chemotherapy for the treatment of cancer
* Known hypersensitivity or contraindication to any component of the test product (study drugs) or diagnostics used
* Participation in another study within eight (8) weeks prior to the study
* Unable to attend all visits required by the protocol

Primary outcomes:
measure: Efficacy: The proportion of patients considered to be "treatment successes" defined by a reduction of at least 50% in the number of draining fistulas at both week 4 and week 8 of an 8 week treatment period
timeFrame: 8 weeks
measure: Safety: Adverse events deemed possibly, probably or definitely related to study drug during 8 weeks of treatment
timeFrame: 8 weeks
Secondary outcomes:
measure: Efficacy: 100% non-draining fistulas at both week 4 and week 8
timeFrame: 8 weeks
measure: Efficacy: Fistula response at Week 8
timeFrame: 8 weeks
measure: Efficacy: Change in CDAI scores from baseline over 8 weeks of treatment
timeFrame: 8 weeks
measure: Safety: Clinical laboratory tests (electrolytes)
timeFrame: 8 weeks
measure: Safety: Development of abscesses
timeFrame: 8 weeks
measure: Safety: Physical examination, vital signs (blood pressure, heart rate, respiration rate and temperature)
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Advanced Clinical Research Institute
state: California
city: San Carlos
country: United States
facility: Digestive Care Medical Center
state: California
city: Winter Park
country: United States
facility: Shafran Gasteroenterology Center
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University, Outpatient Clinical Research Facility
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville, Department of Surgery
state: Kentucky
city: Chevy Chase
country: United States
facility: Metropolitan Gastroenterology Group/Chevy Chase Clinical Research
state: Maryland
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Chesterfield
country: United States
facility: Clinical Research Institute of Michigan, LLC
state: Michigan
city: Fort Lee
country: United States
facility: Drs. Scherf, Chessler, Zingler & Spinnell, MD, PA
state: New Jersey
city: Great Neck
country: United States
facility: Long Island Clinical Research Associates, LLP
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine, IBD Research Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Carolina Digestive Health Associates
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic - Department of Gastroenterology
state: Ohio
city: Hershey
country: United States
facility: The Penn State University, Milton S. Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Digestive Disease Center/MUSC
state: South Carolina
city: Germantown
country: United States
facility: Memphis Gastroenterology Group, PC
state: Tennessee
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Madison
country: United States
facility: Dean Foundation Research Center
state: Wisconsin
city: Innsbruck
country: Austria
facility: Univ Klinik fur Innere Medizin Innsbruck
city: Salzburg
country: Austria
facility: Universitatsklinik fur Innere Medizin I der PMU
city: Wien
country: Austria
facility: AKH Wien - Univ Klinik Innere Med IV
city: Bonheiden
country: Belgium
facility: Imelda General Hospital
city: Genk
country: Belgium
facility: St. Jansziekenhuis/Ziekenhuis Oost-Limburg
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg, University of Leuven
city: Roeselare
country: Belgium
facility: H.-Hartziekenhuis Roeselare-Menen vzw
city: Edmonton
country: Canada
facility: GILDR Group, University of Edmonton
state: Alberta
city: Vancouver
country: Canada
facility: Liver & Intestinal Research Centre
state: British Columbia
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Brno
country: Czech Republic
facility: University Hospital Brno, Internal and Gastroenterology Department
city: Liberec
country: Czech Republic
facility: Regional Hospital Liberec, Department of Gastroenterology
city: Prague 2
country: Czech Republic
facility: University Hospital Prague 2, 4th Department of Internal Medicine
city: Prague 4
country: Czech Republic
facility: Thomayer's University Hospital Prague, 2nd Internal Department
city: Prague 4
country: Czech Republic
facility: Institute for Clinical and Experimental Medicine
city: Amiens
country: France
facility: CHU Hopital Nord, Service de Gastro-enterologie et nutrition
city: Caen
country: France
facility: Hopital de la Cote de Nacre - CHU
city: Grenoble
country: France
facility: CHU de Grenoble - Hopital Nord
city: Lille
country: France
facility: Hopital Claude Huriez, Service des maladies de l'appareil disgestif
city: Marseille
country: France
facility: Hopital Nord, Service de Gastro-Enterologie
city: Montpelier
country: France
facility: Hopital Saint-Eloi, Service de Gastro-enterologie et transplantation
city: Nantes
country: France
facility: CHU Hotel Dieu, Institut des Maladies de l'Appareil Digestif
city: Nice
country: France
facility: CHU de Nice - Hopital de l'Archet 2
city: Paris
country: France
facility: Hopital Leopold Bellan
city: Aachen
country: Germany
facility: Universitatsklinikum Aachen
city: Berlin
country: Germany
facility: Charite-Campus Virchow-Klinikum
city: Frankfurt
country: Germany
facility: Klinikum der Johann-Wolfgang-Goethe Universitat Frankfurt am Main
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitatsklinik Heidelberg Abteilung Gastroenterologie und Hepatologie
city: Kiel
country: Germany
facility: Universitatsklinikum Schleswig-Holstein
city: Munchen
country: Germany
facility: Klinikum rechts der Isar der TUM II
city: Regensburg
country: Germany
facility: Universitatsklinikum Regensburg
city: Rostock
country: Germany
facility: Universitat Rostock - Midizinische Fakultat
city: Tubingen
country: Germany
facility: Medizinische Universitatsklinik Tubingen
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Budapest
country: Hungary
facility: Peterfy Sandor utcai Korhaz-Rendelointezet
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Miskolc
country: Hungary
facility: Miskolc Megyei Jogu Onkormanyzat Semmelweis Oktato Korhaz-Rendelointezet
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem, I.sz. Belgyogyaszati Klinika
city: Haifa
country: Israel
facility: Bnai Zion Medical Center
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Strauss Medical Center
city: Kfar Saba
country: Israel
facility: Meir Hospital
city: Petah Tikva
country: Israel
facility: Rabin Medical Center, Bellinson Hospital
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC, Department of Gastroenterology and Hepatology
city: Katowice
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczny Slaskiej AM
city: Krakow
country: Poland
facility: Zakaznych Szpitala Uniwersyteckiego w Krakowie
city: Lodz
country: Poland
facility: Korektalnej Uniwersytetu Medycznego w Lodzi
city: Olomouc
country: Poland
facility: University Hospital Olomouc, 2nd Internal Department
city: Poznan
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 2 im. Heliodora
city: Warszawa
country: Poland
facility: Samodzielny Publiczny Centralny Szpital
city: Wroclaw
country: Poland
facility: Katedra Klinika Gastroenterologi, Akedemil Medycanej we Wroclawiu
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary, Dept. of Gastroenterology
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
city: Kilmarnock
country: United Kingdom
facility: Crosshouse Hospital
city: Leicester
country: United Kingdom
facility: Leicester General Hospital - GI Research Unit
city: London
country: United Kingdom
facility: University College London Hospital, Dept. of Gastroenterology
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital, Dept. of Gastroenterology
Study officials:
affiliation: Ocera Therapeutics
name: Laurent Fischer, MD
role: STUDY_DIRECTOR
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citation: Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol. 1992 Jun;14(4):309-17. doi: 10.1097/00004836-199206000-00009.
citation: Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):599-603. doi: 10.1038/35079107.
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citation: Schwartz DA, Herdman CR. Review article: The medical treatment of Crohn's perianal fistulas. Aliment Pharmacol Ther. 2004 May 1;19(9):953-67. doi: 10.1111/j.1365-2036.2004.01917.x.
citation: Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999 May 6;340(18):1398-405. doi: 10.1056/NEJM199905063401804.
citation: Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980 May 1;302(18):981-7. doi: 10.1056/NEJM198005013021801.
citation: Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P; ACCENT I Study Group. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002 May 4;359(9317):1541-9. doi: 10.1016/S0140-6736(02)08512-4.
citation: Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004 Feb 26;350(9):876-85. doi: 10.1056/NEJMoa030815.