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

NCT ID: NCT00729872

Last Updated: 2009-09-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-07-31
• Study Completion Date: 2009-09-30

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).

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.

Conditions

Moderately Active Ulcerative Colitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

AG011: low dose

Group Type: EXPERIMENTAL

AG011

Intervention Type: 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.

2

Placebo: low dose

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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.

3

AG011: mid dose

Group Type: EXPERIMENTAL

AG011

Intervention Type: 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.

4

Placebo: mid dose

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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.

5

AG011: high dose

Group Type: EXPERIMENTAL

AG011

Intervention Type: 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.

6

Placebo: high dose

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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.

Interventions

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.

Intervention Type: BIOLOGICAL

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.

Intervention Type: OTHER

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ActoGeniX N.V.

INDUSTRY

Sponsor Role: lead

Responsible Party

ActoGeniX

Principal Investigators

Bernard Coulie, MD PhD

Role: STUDY_CHAIR

Chief Medical Officer ActoGeniX NV

Annegret Van der Aa, PhD

Role: STUDY_DIRECTOR

Project Manager ActoGeniX NV

Severine Vermeire, MD PhD

Role: PRINCIPAL_INVESTIGATOR

UZ Leuven, Belgium

Geert D'Haens, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Imelda Bonheiden, Belgium

Martine De Vos, MD PhD

Role: PRINCIPAL_INVESTIGATOR

UZ Gent, Belgium

Tom Moreels, MD PhD

Role: PRINCIPAL_INVESTIGATOR

UZ Antwerpen, Belgium

Daan Hommes, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center

Erik Hertervig, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Lund University Hospital, Sweden

Curt Tysk, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Orebro University Hospital, Sweden

Robert Lofberg, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Karolinska Institutet

Pierre Paré, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpital St-Sacrement Quebec, Canada

William Barnett, MD PhD

Role: PRINCIPAL_INVESTIGATOR

LHSC - University Campus London, Canada

Brian Bressler, MD PhD

Role: PRINCIPAL_INVESTIGATOR

GI Research Institute Vancouver, Canada

James Gregor, MD PhD

Role: PRINCIPAL_INVESTIGATOR

LHSC - South Street Campus London, Canada

Hillary Steinhart, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Mount Sinai Hospital, Canada

Richmond Sy, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Ottawa Hospital General Campus, Canada

William Depew, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Hotel-Dieu Hospital Kingston, Canada

Donald Daly, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Victoria BC, Canada

Philippe Vergauwe, MD PhD

Role: PRINCIPAL_INVESTIGATOR

AZ Groeninge Campus St.-Niklaas Kortrijk, Belgium

Olivier Dewit, MD PhD

Role: PRINCIPAL_INVESTIGATOR

UCL St. Luc Brussels, Belgium

Locations

Imelda Bonheiden

Bonheiden, , Belgium

UCL St. Luc

Brussels, , Belgium

UZ Antwerpen

Edegem, , Belgium

UZ Gent

Ghent, , Belgium

AZ Groeninge Campus St.-Niklaas

Kortrijk, , Belgium

UZ Leuven

Leuven, , Belgium

GI Research Institute

Vancouver, British Columbia, Canada

The office of Dr. Donald Daly

Victoria, British Columbia, Canada

Hotel Dieu Hospital

Kingston, Ontario, Canada

LHSC - South Street Campus

London, Ontario, Canada

LHSC - University Campus

London, Ontario, Canada

Ottawa Hospital General Campus

Ottawa, Ontario, Canada

Mount Sinai Hospital

Toronto, Ontario, Canada

Hôpital St-Sacrement

Québec, Quebec, Canada

Leiden University Medical Center

Leiden, , Netherlands

Lund University Hospital

Lund, , Sweden

Orebro University Hospital

Örebro, , Sweden

Sophiahemmet

Stockholm, , Sweden

Countries

Belgium; Canada; Netherlands; Sweden

References

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.

Reference Type: BACKGROUND

PMID: 16716759 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25185797 (View on PubMed)

Other Identifiers

AG011-MDUC-201

Identifier Type: -

Identifier Source: org_study_id