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

NCT00729872 | Completed Phase 1 DMC

• 1 other identifier: AG011-MDUC-201
• Study Type: interventional
• Target: 60
• Locations: 4 countries
• Sites: 18

Brief Summary

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).

Conditions

Moderately Active Ulcerative Colitis

Keywords

AG011; Ulcerative Colitis; human Interleukin-10

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (4)

• 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

Study Arms (6)

1

EXPERIMENTAL

AG011: low dose

Biological: AG011

2

PLACEBO COMPARATOR

Placebo: low dose

Other: Placebo

3

EXPERIMENTAL

AG011: mid dose

Biological: AG011

4

PLACEBO COMPARATOR

Placebo: mid dose

Other: Placebo

5

EXPERIMENTAL

AG011: high dose

Biological: AG011

6

PLACEBO COMPARATOR

Placebo: high dose

Other: Placebo

Interventions

AG011 BIOLOGICAL

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.

1; 3; 5

Placebo OTHER

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.

2; 4; 6

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• ActoGeniX N.V.: lead

Study Sites (18)

Imelda Bonheiden

Bonheiden, B-2820, Belgium

Location

UCL St. Luc

Brussels, Belgium

Location

UZ Antwerpen

Edegem, B-2650, Belgium

Location

UZ Gent

Ghent, B-9000, Belgium

Location

AZ Groeninge Campus St.-Niklaas

Kortrijk, Belgium

Location

UZ Leuven

Leuven, B-3000, Belgium

Location

GI Research Institute

Vancouver, British Columbia, V6Z 2K5, Canada

Location

The office of Dr. Donald Daly

Victoria, British Columbia, Canada

Location

Hotel Dieu Hospital

Kingston, Ontario, Canada

Location

LHSC - South Street Campus

London, Ontario, N6A 4G5, Canada

Location

LHSC - University Campus

London, Ontario, N6A 5A5, Canada

Location

Ottawa Hospital General Campus

Ottawa, Ontario, Canada

Location

Mount Sinai Hospital

Toronto, Ontario, Canada

Location

Hôpital St-Sacrement

Québec, Quebec, G1S 4L8, Canada

Location

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

Location

Lund University Hospital

Lund, SE-221 85, Sweden

Location

Orebro University Hospital

Örebro, SE-701 85, Sweden

Location

Sophiahemmet

Stockholm, SE- 114 86, Sweden

Location

Related Publications (2)

• 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.

  PMID: 16716759 BACKGROUND

• 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.

  PMID: 25185797 DERIVED

MeSH Terms

Conditions

Colitis, Ulcerative

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Study Officials

• Bernard Coulie, MD PhD

  Chief Medical Officer ActoGeniX NV

  STUDY CHAIR

• Annegret Van der Aa, PhD

  Project Manager ActoGeniX NV

  STUDY DIRECTOR

• 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

  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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: August 4, 2008
• First Posted: August 8, 2008
• Study Start: July 1, 2008
• Primary Completion: September 1, 2009
• Study Completion: September 1, 2009
• Last Updated: September 10, 2009

Record last verified: 2009-09

Locations

BE (6); SE (3); CA (8); NL (1)