Clinical trial NCT00729872: A Phase 2a Study to Evaluate the Safety, Tolerability, Pharmacodynamics and Efficacy of AG011 in Ulcerative Colitis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Moderately Active Ulcerative Colitis
Keywords: AG011
Ulcerative Colitis
human Interleukin-10
Lead sponsor: ActoGeniX N.V.
Sponsor class: INDUSTRY
First posted: 2008-08-08
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: SAFETY: Adverse Events
timeFrame: day 1, 8 15, 22, 29, 57
measure: SAFETY: Physical Examination (complete or brief)
timeFrame: day -7, 1, 8, 15, 22, 29
measure: SAFETY: Vital signs
timeFrame: day -7, 1, 8, 15, 22, 29, 57
measure: SAFETY: Clinical Laboratory Tests (hematology, serum chemistry, urinalysis)
timeFrame: day -7, 1, 8, 15, 22, 29, 57
measure: SAFETY: Analysis of hIL-10 (systemic exposure) and anti-hIL-10 antibodies (immunogenicity) in plasma
timeFrame: day 1, day 29
measure: SAFETY: Stool Diary
timeFrame: From day -7 until day 29
measure: SAFETY: Other Safety Measures (Stool samples for culture, ova and parasite evaluation and Clostridium difficile assay.
timeFrame: day -7
measure: BIOLOGICAL CONTAINMENT: Evaluation of living, genetically modified micro-organisms in stool samples
timeFrame: day 1, 8, 36
measure: PHARMACODYNAMICS: Biomarkers in blood and colon biopsy samples
timeFrame: day -7, 29
Secondary outcomes:
measure: EFFICACY: Flexible sigmoidoscopy (assessment of inflammation)
timeFrame: Day -7, 29
measure: EFFICACY: Histological assessment of inflammation (biopsy samples)
timeFrame: Day -7, 29
measure: EFFICACY: Disease activity assessments (MCDAS, UCCS, Investigator and Subject Global Ratings)
timeFrame: Day -7, 1, 8, 15, 22, 29, 57
measure: EFFICACY: Laboratory assessments (CRP and fecal calprotectin)
timeFrame: Day 1, 15, 29, 57
Other outcomes:
Locations:
city: Bonheiden
country: Belgium
facility: Imelda Bonheiden
city: Brussels
country: Belgium
facility: UCL St. Luc
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Ghent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge Campus St.-Niklaas
city: Leuven
country: Belgium
facility: UZ Leuven
city: Vancouver
country: Canada
facility: GI Research Institute
state: British Columbia
city: Victoria
country: Canada
facility: The office of Dr. Donald Daly
state: British Columbia
city: Kingston
country: Canada
facility: Hotel Dieu Hospital
state: Ontario
city: London
country: Canada
facility: LHSC - South Street Campus
state: Ontario
city: London
country: Canada
facility: LHSC - University Campus
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital General Campus
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Quebec
country: Canada
facility: Hôpital St-Sacrement
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Lund
country: Sweden
facility: Lund University Hospital
city: Orebro
country: Sweden
facility: Orebro University Hospital
city: Stockholm
country: Sweden
facility: Sophiahemmet
Study officials:
affiliation: Chief Medical Officer ActoGeniX NV
name: Bernard Coulie, MD PhD
role: STUDY_CHAIR
affiliation: Project Manager ActoGeniX NV
name: Annegret Van der Aa, PhD
role: STUDY_DIRECTOR
affiliation: UZ Leuven, Belgium
name: Severine Vermeire, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Imelda Bonheiden, Belgium
name: Geert D'Haens, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZ Gent, Belgium
name: Martine De Vos, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UZ Antwerpen, Belgium
name: Tom Moreels, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Daan Hommes, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lund University Hospital, Sweden
name: Erik Hertervig, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Orebro University Hospital, Sweden
name: Curt Tysk, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska Institutet
name: Robert Lofberg, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital St-Sacrement Quebec, Canada
name: Pierre Paré, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: LHSC - University Campus London, Canada
name: William Barnett, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: GI Research Institute Vancouver, Canada
name: Brian Bressler, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: LHSC - South Street Campus London, Canada
name: James Gregor, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mount Sinai Hospital, Canada
name: Hillary Steinhart, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ottawa Hospital General Campus, Canada
name: Richmond Sy, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hotel-Dieu Hospital Kingston, Canada
name: William Depew, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Victoria BC, Canada
name: Donald Daly, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ Groeninge Campus St.-Niklaas Kortrijk, Belgium
name: Philippe Vergauwe, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCL St. Luc Brussels, Belgium
name: Olivier Dewit, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.