Safety and Efficacy of AST-120 in Mild to Moderate Crohn's Patients With Fistulas

Inflammatory Bowel Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00321412
• Other study ID #: AST001
• Status: Completed
• Phase: Phase 3
• First received: May 1, 2006
• Last updated: May 27, 2014
• Start date: March 2006
• Est. completion date: September 2008

Study information

• Verified date: May 2014
• Source: Ocera Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyGermany: Federal Institute for Drugs and Medical DevicesFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentCzech Republic: State Institute for Drug ControlPoland: Ministry of HealthNetherlands: Dutch Health Care InspectorateHungary: National Institute of PharmacyAustria: Agency for Health and Food SafetyIsrael: Ministry of Health
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 191
• Est. completion date: September 2008
• Est. primary completion date: March 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fistula
• Inflammatory Bowel Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Intestinal Fistula

Intervention

Drug:
• AST-120
oral, sachet, 2 grams three times daily for 8 weeks

Locations

Country	Name	City	State
Austria	Univ Klinik fur Innere Medizin Innsbruck	Innsbruck
Austria	Universitatsklinik fur Innere Medizin I der PMU	Salzburg
Austria	AKH Wien - Univ Klinik Innere Med IV	Wien
Belgium	Imelda General Hospital	Bonheiden
Belgium	St. Jansziekenhuis/Ziekenhuis Oost-Limburg	Genk
Belgium	University Hospital Gasthuisberg, University of Leuven	Leuven
Belgium	H.-Hartziekenhuis Roeselare-Menen vzw	Roeselare
Canada	GILDR Group, University of Edmonton	Edmonton	Alberta
Canada	McMaster University Medical Centre	Hamilton	Ontario
Canada	London Health Sciences Center	London	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Liver & Intestinal Research Centre	Vancouver	British Columbia
Czech Republic	University Hospital Brno, Internal and Gastroenterology Department	Brno
Czech Republic	Regional Hospital Liberec, Department of Gastroenterology	Liberec
Czech Republic	University Hospital Prague 2, 4th Department of Internal Medicine	Prague 2
Czech Republic	Institute for Clinical and Experimental Medicine	Prague 4
Czech Republic	Thomayer's University Hospital Prague, 2nd Internal Department	Prague 4
France	CHU Hopital Nord, Service de Gastro-enterologie et nutrition	Amiens
France	Hopital de la Cote de Nacre - CHU	Caen
France	CHU de Grenoble - Hopital Nord	Grenoble
France	Hopital Claude Huriez, Service des maladies de l'appareil disgestif	Lille
France	Hopital Nord, Service de Gastro-Enterologie	Marseille
France	Hopital Saint-Eloi, Service de Gastro-enterologie et transplantation	Montpelier
France	CHU Hotel Dieu, Institut des Maladies de l'Appareil Digestif	Nantes
France	CHU de Nice - Hopital de l'Archet 2	Nice
France	Hopital Leopold Bellan	Paris
Germany	Universitatsklinikum Aachen	Aachen
Germany	Charite-Campus Virchow-Klinikum	Berlin
Germany	Klinikum der Johann-Wolfgang-Goethe Universitat Frankfurt am Main	Frankfurt
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitatsklinik Heidelberg Abteilung Gastroenterologie und Hepatologie	Heidelberg
Germany	Universitatsklinikum Schleswig-Holstein	Kiel
Germany	Klinikum rechts der Isar der TUM II	Munchen
Germany	Universitatsklinikum Regensburg	Regensburg
Germany	Universitat Rostock - Midizinische Fakultat	Rostock
Germany	Medizinische Universitatsklinik Tubingen	Tubingen
Germany	Universitatsklinikum Ulm	Ulm
Hungary	Peterfy Sandor utcai Korhaz-Rendelointezet	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Miskolc Megyei Jogu Onkormanyzat Semmelweis Oktato Korhaz-Rendelointezet	Miskolc
Hungary	Szegedi Tudomanyegyetem, I.sz. Belgyogyaszati Klinika	Szeged
Israel	Bnai Zion Medical Center	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Strauss Medical Center	Jerusalem
Israel	Meir Hospital	Kfar Saba
Israel	Rabin Medical Center, Bellinson Hospital	Petah Tikva
Israel	Sheba Medical Center	Ramat Gan
Israel	Kaplan Medical Center	Rehovot
Netherlands	Erasmus MC, Department of Gastroenterology and Hepatology	Rotterdam
Poland	Samodzielny Publiczny Centralny Szpital Kliniczny Slaskiej AM	Katowice
Poland	Zakaznych Szpitala Uniwersyteckiego w Krakowie	Krakow
Poland	Korektalnej Uniwersytetu Medycznego w Lodzi	Lodz
Poland	University Hospital Olomouc, 2nd Internal Department	Olomouc
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 2 im. Heliodora	Poznan
Poland	Samodzielny Publiczny Centralny Szpital	Warszawa
Poland	Katedra Klinika Gastroenterologi, Akedemil Medycanej we Wroclawiu	Wroclaw
United Kingdom	Bristol Royal Infirmary, Dept. of Gastroenterology	Bristol
United Kingdom	Countess of Chester Hospital	Chester
United Kingdom	Crosshouse Hospital	Kilmarnock
United Kingdom	Leicester General Hospital - GI Research Unit	Leicester
United Kingdom	University College London Hospital, Dept. of Gastroenterology	London
United Kingdom	John Radcliffe Hospital, Dept. of Gastroenterology	Oxford
United States	Advanced Clinical Research Institute	Anaheim	California
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Digestive Disease Center/MUSC	Charleston	South Carolina
United States	Carolina Digestive Health Associates	Charlotte	North Carolina
United States	Clinical Research Institute of Michigan, LLC	Chesterfield	Michigan
United States	Metropolitan Gastroenterology Group/Chevy Chase Clinical Research	Chevy Chase	Maryland
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Cleveland Clinic - Department of Gastroenterology	Cleveland	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Drs. Scherf, Chessler, Zingler & Spinnell, MD, PA	Fort Lee	New Jersey
United States	Memphis Gastroenterology Group, PC	Germantown	Tennessee
United States	Long Island Clinical Research Associates, LLP	Great Neck	New York
United States	The Penn State University, Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Indiana University, Outpatient Clinical Research Facility	Indianapolis	Indiana
United States	University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	University of Louisville, Department of Surgery	Louisville	Kentucky
United States	Dean Foundation Research Center	Madison	Wisconsin
United States	Mount Sinai School of Medicine, IBD Research Center	New York	New York
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Rochester Medical Center	Rochester	New York
United States	Digestive Care Medical Center	San Carlos	California
United States	University of Washington	Seattle	Washington
United States	Shafran Gasteroenterology Center	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Ocera Therapeutics

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  Czech Republic,  France,  Germany,  Hungary,  Israel,  Netherlands,  Poland,  United Kingdom, 

References & Publications (14)

Best WR, Becktel JM, Singleton JW. Rederived values of the eight coefficients of the Crohn's Disease Activity Index (CDAI). Gastroenterology. 1979 Oct;77(4 Pt 2):843-6. — View Citation

Farmer RG, Hawk WA, Turnbull RB Jr. Clinical patterns in Crohn's disease: a statistical study of 615 cases. Gastroenterology. 1975 Apr;68(4 Pt 1):627-35. — View Citation

Gray BK, Lockhartmummery HE, Morson BC. Crohn's disease of the anal region. Gut. 1965 Dec;6(6):515-24. — View 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. — View Citation

Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol. 1992 Jun;14(4):309-17. — View Citation

Hellers G, Bergstrand O, Ewerth S, Holmström B. Occurrence and outcome after primary treatment of anal fistulae in Crohn's disease. Gut. 1980 Jun;21(6):525-7. — View Citation

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard 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. — View Citation

Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):603-6. — View 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. — View 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. — View 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. — View 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. Review. — View Citation

Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology. 2002 Apr;122(4):875-80. — View Citation

Schwartz DA, Pemberton JH, Sandborn WJ. Diagnosis and treatment of perianal fistulas in Crohn disease. Ann Intern Med. 2001 Nov 20;135(10):906-18. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		8 weeks	No
Primary	Safety: Adverse events deemed possibly, probably or definitely related to study drug during 8 weeks of treatment		8 weeks	Yes
Secondary	Efficacy: 100% non-draining fistulas at both week 4 and week 8		8 weeks	No
Secondary	Efficacy: Fistula response at Week 8		8 weeks	No
Secondary	Efficacy: Change in CDAI scores from baseline over 8 weeks of treatment		8 weeks	No
Secondary	Safety: Clinical laboratory tests (electrolytes)		8 weeks	Yes
Secondary	Safety: Development of abscesses		8 weeks	Yes
Secondary	Safety: Physical examination, vital signs (blood pressure, heart rate, respiration rate and temperature)		8 weeks	Yes