Clinical trial NCT01759056: Evaluation of an Oral Anti-TNF Antibody in Patients With Active Ulcerative Colitis
Official title: A Multicenter, Double-Blind, Placebo-Controlled, Ascending-Dose, Repeat-Dose Safety and Pharmacokinetic Investigation of a Delayed-Release, Enteric-Coated Capsule Formulation of AVX 470 [Anti-TNF (Tumor Necrosis Factor) Globulin (Bovine)] in Patients With Active Ulcerative Colitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Ulcerative Colitis
Keywords: Ulcerative colitis
Lead sponsor: Avaxia Biologics, Incorporated
Sponsor class: INDUSTRY
First posted: 2013-01-02
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and tolerability as well as the pharmacodynamic effects of multiple doses of AVX-470 administered orally in patients with active ulcerative colitis.

Detailed description: There is a significant unmet medical need for effective oral pharmacologic therapies for inflammatory bowel diseases such as ulcerative colitis. Current anti-TNF therapies, including infliximab and adalimumab, are effective treatments for these conditions, but they must be administered by intravenous or subcutaneous injection. The major safety concerns associated with the use of injectable anti-TNF therapies are infection, demyelinating disease, and lymphoma, all of which are the result of systemic exposure. These uncommon but serious side effects have limited the use of systemic anti-TNF antibody therapy to patients with severe disease that have failed to respond to first-line treatments.

AVX-470 is purified immunoglobulin (Ig) from the colostrum (early milk) of cows immunized with recombinant human tumor necrosis factor (rhTNF). AVX-470 is formulated in delayed-release enteric-coated capsules designed to protect the capsule contents from gastric acids following oral administration and to provide localized delivery to sites of inflammation in the distal intestine. Prior clinical experience with bovine Ig therapies in other human diseases suggests that AVX-470 will not be absorbed to any significant extent, meaning that systemic exposure could be minimized. The development of oral anti-TNF therapy targeting local intestinal disease activity might reduce the risks associated with injectable anti-TNF therapy and allow the convenience of oral dosing.

The present study is a first-in-human, Phase 1 clinical study. It is primarily intended to evaluate the safety and tolerability of multiple doses of AVX-470 administered orally to patients with active ulcerative colitis.

Animal models of ulcerative colitis using a mouse-specific TNF antibody derived from bovine colostrum demonstrated a 50% or more reduction in tissue TNF, TNF-messenger ribonucleic acid (mRNA), interleukin (IL)-6 mRNA, and myeloperoxidase and lowering of colonic inflammatory activity. Twenty-eight-day toxicology studies demonstrated no clinical or histologic findings in exposures above the intended clinical dose range.

Eligibility criteria: Inclusion Criteria:

* Men or women aged 18 75, inclusive
* Established diagnosis of ulcerative colitis involving the sigmoid colon or proximal segments of bowel
* Total Mayo score between 5-12, inclusive, with endoscopic subscore of the Mayo score ≥ 2 and \> 15 cm of involvement beyond the anal verge

Exclusion Criteria:

* Women with a positive pregnancy test, who are breastfeeding, or who intend to become pregnant during the course of the study
* Diagnosis of Crohn's disease, microscopic colitis or indeterminate colitis
* Presence of ileostomy or colostomy, or history of prior colon resection
* Patients with planned hospitalization or surgery during the course of the study
* Known allergy to milk proteins, red meat or cornstarch
* Stools positive for enteric infection, including parasitic, or C. difficile toxin within 28 days of screening
* Documented presence of Hetatitis B (HBsAg), Hepatitis C (HCV), or HIV
* Presence of dysplasia of any grade on colonoscopic biopsies
* Treatment for cancer (excluding non-melanomatous cancer of the skin or cervical carcinoma in situ) or lymphoproliferative disorder (including lymphoma) within 5 years
* History of tuberculosis (TB) or Listeria infection, or known exposure to another person with active TB disease within 12 weeks of screening; or history of past or current infection with different opportunistic infections
* History of TNF inhibitor (infliximab, adalimumab or certolizumab pegol) use with primary treatment failure. Secondary treatment failures due to intolerance, allergic reaction, or loss of response will not constitute a basis for exclusion. Oral immunosuppressives, mesalamine, and corticosteroids (up to 20mg of prednisone per day) will be permitted so long as these medications are stable for defined periods of time before study participation commences.

Primary outcomes:
measure: Safety and tolerability of AVX-470 over 28 days of treatment
timeFrame: 5 weeks
Secondary outcomes:
measure: Pharmacokinetics (serum, stool and gastrointestinal mucosal tissue levels) of AVX-470
timeFrame: 4 weeks
measure: Measure the induction of or change in a human anti-bovine immunoglobulin antibody (HABA) response to AVX 470
timeFrame: 4 weeks
Other outcomes:
measure: Clinical response to AVX 470 in ulcerative colitis, as assessed by the total Mayo score and subscores, after 28 days of treatment compared to Baseline
timeFrame: 4 weeks
measure: Effect of AVX 470 on endoscopic healing in ulcerative colitis, as assessed by the endoscopic subscore of the total Mayo score and the Ulcerative Colitis Index of Severity (UCEIS), after 28 days of treatment compared to Baseline
timeFrame: 4 weeks
measure: Evaluate the effects of AVX 470 on biomarkers of ulcerative colitis activity over 28 days of treatment compared to Baseline
timeFrame: 4 weeks
Locations:
city: Anaheim
country: United States
facility: Anaheim Clinical Trials
state: California
city: Lakewood
country: United States
facility: Rocky Mountain Gastroenterology Associates
state: Colorado
city: Winter Park
country: United States
facility: Shafran Gastroenterology Center
state: Florida
city: Chevy Chase
country: United States
facility: Chevy Chase Clinical Research
state: Maryland
city: Chesterfield
country: United States
facility: Clinical Research Institute of Michigan
state: Michigan
city: Mexico
country: United States
facility: Center for Digestive and Liver Disease
state: Missouri
city: Columbus
country: United States
facility: Remington-Davis, Inc.
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Foundation for Digestive Research
state: Oklahoma
city: Nashville
country: United States
facility: Nashville Medical Research Institute
state: Tennessee
city: Gent
country: Belgium
facility: Gastro-Enterologie
city: Leuven
country: Belgium
facility: Gastro-enterologie
city: Edmonton
country: Canada
facility: The Northern Alberta Clinical Trials and Research Centre
state: Alberta
city: Toronto
country: Canada
facility: Toronto Digestive Disease Associates
state: Ontario
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Orvos- és Egészségtudományi Centrum
city: Debrecen
country: Hungary
facility: Kenézy Kórház Rendelöintézet Egészségügyi Szolgáltató Kft.
Study officials:
affiliation: Avaxia Biologics, Incorporated
name: Scott Harris, MD
role: STUDY_DIRECTOR
References:
citation: Harris MS, Hartman D, Lemos BR, Erlich EC, Spence S, Kennedy S, Ptak T, Pruitt R, Vermeire S, Fox BS. AVX-470, an Orally Delivered Anti-Tumour Necrosis Factor Antibody for Treatment of Active Ulcerative Colitis: Results of a First-in-Human Trial. J Crohns Colitis. 2016 Jun;10(6):631-40. doi: 10.1093/ecco-jcc/jjw036. Epub 2016 Jan 28.
citation: Hartman DS, Tracey DE, Lemos BR, Erlich EC, Burton RE, Keane DM, Patel R, Kim S, Bhol KC, Harris MS, Fox BS. Effects of AVX-470, an Oral, Locally Acting Anti-Tumour Necrosis Factor Antibody, on Tissue Biomarkers in Patients with Active Ulcerative Colitis. J Crohns Colitis. 2016 Jun;10(6):641-9. doi: 10.1093/ecco-jcc/jjw026. Epub 2016 Jan 22.