A Phase 2a Study to Evaluate the Safety, Tolerability, Pharmacodynamics and Efficacy of AG011 in Ulcerative Colitis

This study has been completed.
Sponsor:
Information provided by:
ActoGeniX N.V.
ClinicalTrials.gov Identifier:
NCT00729872
First received: August 4, 2008
Last updated: September 9, 2009
Last verified: September 2009
  Purpose

The purpose of this study is to verify the safety and tolerability of AG011 (genetically modified L. lactis that has been engineered to secrete human Interleukin-10), and to determine whether AG011 can successfully treat the symptoms of moderately active Ulcerative Colitis (UC).


Condition Intervention Phase
Moderately Active Ulcerative Colitis
Biological: AG011
Other: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2a Randomized, Placebo-Controlled, Double-Blind, Multi-Center Dose Escalation Study, to Evaluate the Safety, Tolerability, Pharmacodynamics and Efficacy of AG011, in Subjects With Moderately Active Ulcerative Colitis

Resource links provided by NLM:


Further study details as provided by ActoGeniX N.V.:

Primary Outcome Measures:
  • SAFETY: Adverse Events [ Time Frame: day 1, 8 15, 22, 29, 57 ] [ Designated as safety issue: Yes ]
  • SAFETY: Physical Examination (complete or brief) [ Time Frame: day -7, 1, 8, 15, 22, 29 ] [ Designated as safety issue: Yes ]
  • SAFETY: Vital signs [ Time Frame: day -7, 1, 8, 15, 22, 29, 57 ] [ Designated as safety issue: Yes ]
  • SAFETY: Clinical Laboratory Tests (hematology, serum chemistry, urinalysis) [ Time Frame: day -7, 1, 8, 15, 22, 29, 57 ] [ Designated as safety issue: Yes ]
  • SAFETY: Analysis of hIL-10 (systemic exposure) and anti-hIL-10 antibodies (immunogenicity) in plasma [ Time Frame: day 1, day 29 ] [ Designated as safety issue: Yes ]
  • SAFETY: Stool Diary [ Time Frame: From day -7 until day 29 ] [ Designated as safety issue: Yes ]
  • SAFETY: Other Safety Measures (Stool samples for culture, ova and parasite evaluation and Clostridium difficile assay. [ Time Frame: day -7 ] [ Designated as safety issue: Yes ]
  • BIOLOGICAL CONTAINMENT: Evaluation of living, genetically modified micro-organisms in stool samples [ Time Frame: day 1, 8, 36 ] [ Designated as safety issue: No ]
  • PHARMACODYNAMICS: Biomarkers in blood and colon biopsy samples [ Time Frame: day -7, 29 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • EFFICACY: Flexible sigmoidoscopy (assessment of inflammation) [ Time Frame: Day -7, 29 ] [ Designated as safety issue: No ]
  • EFFICACY: Histological assessment of inflammation (biopsy samples) [ Time Frame: Day -7, 29 ] [ Designated as safety issue: No ]
  • EFFICACY: Disease activity assessments (MCDAS, UCCS, Investigator and Subject Global Ratings) [ Time Frame: Day -7, 1, 8, 15, 22, 29, 57 ] [ Designated as safety issue: No ]
  • EFFICACY: Laboratory assessments (CRP and fecal calprotectin) [ Time Frame: Day 1, 15, 29, 57 ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: July 2008
Study Completion Date: September 2009
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
AG011: low dose
Biological: AG011
Capsules (low, mid or high dose), twice daily for 28 days, combined with Enema (low, mid or high dose respectively), once daily for 28 days.
Placebo Comparator: 2
Placebo: low dose
Other: Placebo
Capsules (matching placebo for low, mid or high dose), twice daily for 28 days, combined with Enema (matching placebo for low, mid or high dose respectively), once daily for 28 days.
Experimental: 3
AG011: mid dose
Biological: AG011
Capsules (low, mid or high dose), twice daily for 28 days, combined with Enema (low, mid or high dose respectively), once daily for 28 days.
Placebo Comparator: 4
Placebo: mid dose
Other: Placebo
Capsules (matching placebo for low, mid or high dose), twice daily for 28 days, combined with Enema (matching placebo for low, mid or high dose respectively), once daily for 28 days.
Experimental: 5
AG011: high dose
Biological: AG011
Capsules (low, mid or high dose), twice daily for 28 days, combined with Enema (low, mid or high dose respectively), once daily for 28 days.
Placebo Comparator: 6
Placebo: high dose
Other: Placebo
Capsules (matching placebo for low, mid or high dose), twice daily for 28 days, combined with Enema (matching placebo for low, mid or high dose respectively), once daily for 28 days.

Detailed Description:

The purpose of this study is to verify the safety and tolerability of AG011 and to determine whether AG011 can successfully treat the symptoms of Ulcerative Colitis (UC). Three different dosages will be used in reference to a placebo.

AG011 is an experimental medication. It has been developed as potential treatment for moderately active UC.

AG011 is the clinical formulation of a genetically modified L. lactis that has been engineered to secrete human Interleukin-10 (hIL-10). By delivering hIL-10 locally at inflamed tissue in the intestine, it is believed that, compared to hIL-10 given by injection, the effectiveness may be increased, with fewer adverse effects.

Study medication will be provided in capsule and enema (topical rectal application) forms by ActoGeniX NV.

Subjects will be entered sequentially into one of three dose groups, starting from the lowest dose group. Within each of the first two dose groups, 15 subjects will be entered. Within the highest dose group, 30 subjects will be entered. Within each dose group, subjects will be randomly assigned in a 2:1 ratio to receive either AG011 or placebo for 28 days.

Timely monitoring of safety data is planned for the study, such that subject enrollment can continue without interruption for the purpose of data collection between dose groups. Safety and tolerability will be closely monitored by the Clinical Safety Specialist (CSS) assigned to the study. The CSS will review adverse events and laboratory safety data and report any safety concerns to the Sponsor and a Data Safety Monitoring Committee (DSMC).

At least 8 subjects must have safely completed study treatment for 28 days at a specific dose level, prior to escalation to the next dose group. The DSMC will convene to assess safety data when 8 subjects have completed study treatment for 28 days at the specific dose level. The role of the DSMC for the study will be complete when all subjects in the study have completed study treatment.

For those patients randomized within the active group, UC symptoms could improve. As a result of the information gathered by this study, the knowledge and understanding of UC could improve.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or non-pregnant, non-lactating females, 18 years of age or older. Females of child bearing potential must have negative serum or urine pregnancy tests at the screening visit and throughout the study, and must use a hormonal (oral, implantable or injectable) or barrier method of birth control throughout the study. Females unable to bear children must have documentation of such in the case report form (i.e. tubal ligation, hysterectomy, or post menopausal [defined as a minimum of one year since the last menstrual period]).
  • Documented diagnosis of UC with a minimum disease extent of 15 cm from the anal verge.
  • Presence of friability on endoscopy, with minimum of Grade 2 (modified Baron score) changes at approximately 15 cm or more from the anal verge.
  • Minimum Mayo Clinic Disease Activity Score of 5, with a score of at least 1 on both the stool frequency and rectal bleeding components.
  • Receiving 5-ASA treatment for at least two months and a stable dose of oral 5 ASA for at least two weeks prior to randomization. Concurrent treatment with prednisone, or equivalent glucocorticoid ≤ 20 mg/day is acceptable as follows: minimum dosing of 4 weeks prior to screening AND stable dose for 2 weeks prior to screening AND expected to remain on a constant dose during the trial. Use of 5-ASA compounds is not required for those subjects who have failed treatment with 5-ASA compounds, or are allergic or intolerant.
  • Hepatic function (AST, ALT, total bilirubin, alkaline phosphatase, LDH) ≤ 2 times the upper limit of the normal range.
  • Adequate renal function, as evidenced by serum creatinine ≤ 1.5 times the upper limit of the normal range.
  • Hemoglobin ≥ 10 g/dL.
  • ANC ≥ 1.5 x 10E9/L (1,500 mm3).
  • Lymphocyte count ≥ 0.1 x 10E3/μL.
  • Platelet count ≥ 100 x 10E9/L (100,000/mm3).
  • Ability of subject to participate fully in all aspects of this clinical trial.
  • Written informed consent must be obtained and documented.

Exclusion Criteria:

  • Exhibiting severe ulcerative colitis as defined by the following criteria: ≥ 6 bloody stools daily with one or more of the following: oral temperature > 37.8 °C or > 100.0 °F, pulse > 90/min, hemoglobin < 10 g/dL.
  • Crohn's disease.
  • History of colectomy or partial colectomy.
  • Clostridium (C.) difficile positive at screening visit or treated for C. difficile within the 4 weeks prior to randomization
  • Treatment with antibiotics or probiotics at screening
  • Treatment with cyclosporine, methotrexate, azathioprine, 6-MP, infliximab, adalimumab or other immunosuppressants/biologics within 4 weeks prior to randomization
  • Use of rectal steroids or 5-ASA enemas within 2 weeks prior to randomization.
  • Clinically significant active infection.
  • Known chronic liver disease.
  • Serious underlying disease other than UC in the opinion of the investigator.
  • Alcohol or illicit drug consumption, which in the opinion of the investigator, may interfere with the subject's ability to comply with the study procedures
  • Active psychiatric problems, which in the opinion of the investigator, may interfere with the subject's ability to comply with the study procedures.
  • History of malignancy other than basal or squamous cell cancer of the skin that has been removed, or carcinoma in situ of the cervix that has been adequately treated.
  • History of dysplasia in colonic biopsies.
  • Receiving any investigational therapy or any approved therapy for investigational use within 30 days or 5 half-lives prior to randomization (whichever is longer).
  • Pregnant or lactating women.
  • Prior enrollment in the current study and had received study treatment.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00729872

Locations
Belgium
Imelda Bonheiden
Bonheiden, Belgium, B-2820
UCL St. Luc
Brussels, Belgium
UZ Antwerpen
Edegem, Belgium, B-2650
UZ Gent
Ghent, Belgium, B-9000
AZ Groeninge Campus St.-Niklaas
Kortrijk, Belgium
UZ Leuven
Leuven, Belgium, B-3000
Canada, British Columbia
GI Research Institute
Vancouver, British Columbia, Canada, V6Z 2K5
The office of Dr. Donald Daly
Victoria, British Columbia, Canada
Canada, Ontario
Hotel Dieu Hospital
Kingston, Ontario, Canada
LHSC - University Campus
London, Ontario, Canada, N6A 5A5
LHSC - South Street Campus
London, Ontario, Canada, N6A 4G5
Ottawa Hospital General Campus
Ottawa, Ontario, Canada
Mount Sinai Hospital
Toronto, Ontario, Canada
Canada
Hôpital St-Sacrement
Quebec, Canada, G1S 4L8
Netherlands
Leiden University Medical Center
Leiden, Netherlands, 2333 ZA
Sweden
Lund University Hospital
Lund, Sweden, SE-221 85
Orebro University Hospital
Orebro, Sweden, SE-701 85
Sophiahemmet
Stockholm, Sweden, SE- 114 86
Sponsors and Collaborators
ActoGeniX N.V.
Investigators
Study Chair: Bernard Coulie, MD PhD Chief Medical Officer ActoGeniX NV
Study Director: Annegret Van der Aa, PhD Project Manager ActoGeniX NV
Principal Investigator: Severine Vermeire, MD PhD UZ Leuven, Belgium
Principal Investigator: Geert D'Haens, MD PhD Imelda Bonheiden, Belgium
Principal Investigator: Martine De Vos, MD PhD UZ Gent, Belgium
Principal Investigator: Tom Moreels, MD PhD UZ Antwerpen, Belgium
Principal Investigator: Daan Hommes, MD PhD Leiden University Medical Center
Principal Investigator: Erik Hertervig, MD PhD Lund University Hospital, Sweden
Principal Investigator: Curt Tysk, MD PhD Orebro University Hospital, Sweden
Principal Investigator: Robert Lofberg, MD PhD Karolinska Institutet, Sweden
Principal Investigator: Pierre Paré, MD PhD Hôpital St-Sacrement Quebec, Canada
Principal Investigator: William Barnett, MD PhD LHSC - University Campus London, Canada
Principal Investigator: Brian Bressler, MD PhD GI Research Institute Vancouver, Canada
Principal Investigator: James Gregor, MD PhD LHSC - South Street Campus London, Canada
Principal Investigator: Hillary Steinhart, MD PhD Mount Sinai Hospital, Canada
Principal Investigator: Richmond Sy, MD PhD Ottawa Hospital General Campus, Canada
Principal Investigator: William Depew, MD PhD Hotel-Dieu Hospital Kingston, Canada
Principal Investigator: Donald Daly, MD PhD Victoria BC, Canada
Principal Investigator: Philippe Vergauwe, MD PhD AZ Groeninge Campus St.-Niklaas Kortrijk, Belgium
Principal Investigator: Olivier Dewit, MD PhD UCL St. Luc Brussels, Belgium
  More Information

Publications:
Responsible Party: Bernard Coulie, VP Research and Development, ActoGeniX
ClinicalTrials.gov Identifier: NCT00729872     History of Changes
Other Study ID Numbers: AG011-MDUC-201
Study First Received: August 4, 2008
Last Updated: September 9, 2009
Health Authority: Belgium: Commissie Medische Ethiek UZ Leuven (leading EC), Federal Agency for Medicines and Health Products, Division of Biosafety and Biotechnology
Netherlands: Netherlands Ministry of Housing, Spatial planning and the Environment, Central Committee on Research involving Human Subjects, bureau GGO
Sweden: Medical Products Agency, Regional Ethical Examining Board in Lund second division (leading EC)
Canada: Health Canada, Research Ethics Board

Keywords provided by ActoGeniX N.V.:
AG011
Ulcerative Colitis
human Interleukin-10

Additional relevant MeSH terms:
Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Inflammatory Bowel Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on April 15, 2014