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

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

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).

Study Overview

• Status: Completed
• Conditions: Moderately Active Ulcerative Colitis
• Intervention / Treatment: Biological: AG011; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium, B-2820
    • Imelda Bonheiden
  • Brussels, Belgium
    • UCL St. Luc
  • Edegem, Belgium, B-2650
    • UZ Antwerpen
  • Ghent, Belgium, B-9000
    • UZ Gent
  • Kortrijk, Belgium
    • AZ Groeninge Campus St.-Niklaas
  • Leuven, Belgium, B-3000
    • UZ Leuven
• Canada
  • Quebec, Canada, G1S 4L8
    • Hopital St-Sacrement
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2K5
      • GI Research Institute
    • Victoria, British Columbia, Canada
      • The office of Dr. Donald Daly
  • Ontario
    • Kingston, Ontario, Canada
      • Hotel Dieu Hospital
    • London, Ontario, Canada, N6A 4G5
      • LHSC - South Street Campus
    • London, Ontario, Canada, N6A 5A5
      • LHSC - University Campus
    • Ottawa, Ontario, Canada
      • Ottawa Hospital General Campus
    • Toronto, Ontario, Canada
      • Mount Sinai Hospital
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
• Sweden
  • Lund, Sweden, SE-221 85
    • Lund University Hospital
  • Orebro, Sweden, SE-701 85
    • Orebro University Hospital
  • Stockholm, Sweden, SE- 114 86
    • Sophiahemmet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
SAFETY: Adverse Events	day 1, 8 15, 22, 29, 57
SAFETY: Physical Examination (complete or brief)	day -7, 1, 8, 15, 22, 29
SAFETY: Vital signs	day -7, 1, 8, 15, 22, 29, 57
SAFETY: Clinical Laboratory Tests (hematology, serum chemistry, urinalysis)	day -7, 1, 8, 15, 22, 29, 57
SAFETY: Analysis of hIL-10 (systemic exposure) and anti-hIL-10 antibodies (immunogenicity) in plasma	day 1, day 29
SAFETY: Stool Diary	From day -7 until day 29
SAFETY: Other Safety Measures (Stool samples for culture, ova and parasite evaluation and Clostridium difficile assay.	day -7
BIOLOGICAL CONTAINMENT: Evaluation of living, genetically modified micro-organisms in stool samples	day 1, 8, 36
PHARMACODYNAMICS: Biomarkers in blood and colon biopsy samples	day -7, 29

Secondary Outcome Measures

Outcome Measure	Time Frame
EFFICACY: Flexible sigmoidoscopy (assessment of inflammation)	Day -7, 29
EFFICACY: Histological assessment of inflammation (biopsy samples)	Day -7, 29
EFFICACY: Disease activity assessments (MCDAS, UCCS, Investigator and Subject Global Ratings)	Day -7, 1, 8, 15, 22, 29, 57
EFFICACY: Laboratory assessments (CRP and fecal calprotectin)	Day 1, 15, 29, 57

Collaborators and Investigators

• Sponsor: 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, Örebro University Hospital, Sweden; Principal Investigator: Robert Lofberg, MD PhD, Karolinska Institutet; 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

Publications and helpful links

General Publications

• Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin Gastroenterol Hepatol. 2006 Jun;4(6):754-9. doi: 10.1016/j.cgh.2006.03.028. Epub 2006 May 22.
• Robert S, Steidler L. Recombinant Lactococcus lactis can make the difference in antigen-specific immune tolerance induction, the Type 1 Diabetes case. Microb Cell Fact. 2014 Aug 29;13 Suppl 1(Suppl 1):S11. doi: 10.1186/1475-2859-13-S1-S11. Epub 2014 Aug 29.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (ACTUAL): September 1, 2009
• Study Completion (ACTUAL): September 1, 2009

Study Registration Dates

• First Submitted: August 4, 2008
• First Submitted That Met QC Criteria: August 4, 2008
• First Posted (ESTIMATE): August 8, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): September 10, 2009
• Last Update Submitted That Met QC Criteria: September 9, 2009
• Last Verified: September 1, 2009

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; AG011; human Interleukin-10
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: AG011-MDUC-201