Evaluation of an Oral Anti-TNF Antibody in Patients With Active Ulcerative Colitis

Ulcerative Colitis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01759056
• Other study ID #: AB1101
• Secondary ID: 2012-004850-27
• Status: Completed
• Phase: Phase 1
• First received: December 24, 2012
• Last updated: March 4, 2014
• Start date: February 2013
• Est. completion date: December 2013

Study information

• Verified date: February 2014
• Source: Avaxia Biologics, Incorporated
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Drug:
• AVX 470
active comparator
• Placebo

Locations

Country	Name	City	State
Belgium	Gastro-Enterologie	Gent
Belgium	Gastro-enterologie	Leuven
Canada	The Northern Alberta Clinical Trials and Research Centre	Edmonton	Alberta
Canada	Toronto Digestive Disease Associates	Toronto	Ontario
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem Orvos- és Egészségtudományi Centrum	Debrecen
Hungary	Kenézy Kórház Rendelöintézet Egészségügyi Szolgáltató Kft.	Debrecen
United States	Anaheim Clinical Trials	Anaheim	California
United States	Clinical Research Institute of Michigan	Chesterfield	Michigan
United States	Chevy Chase Clinical Research	Chevy Chase	Maryland
United States	Remington-Davis, Inc.	Columbus	Ohio
United States	Rocky Mountain Gastroenterology Associates	Lakewood	Colorado
United States	Center for Digestive and Liver Disease	Mexico	Missouri
United States	Nashville Medical Research Institute	Nashville	Tennessee
United States	Oklahoma Foundation for Digestive Research	Oklahoma City	Oklahoma
United States	Shafran Gastroenterology Center	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Avaxia Biologics, Incorporated

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Hungary, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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		4 weeks	Yes
Other	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		4 weeks	Yes
Other	Evaluate the effects of AVX 470 on biomarkers of ulcerative colitis activity over 28 days of treatment compared to Baseline		4 weeks	Yes
Primary	Safety and tolerability of AVX-470 over 28 days of treatment	Assessments weekly during treatment and 1 week post treatment	5 weeks	Yes
Secondary	Pharmacokinetics (serum, stool and gastrointestinal mucosal tissue levels) of AVX-470		4 weeks	Yes
Secondary	Measure the induction of or change in a human anti-bovine immunoglobulin antibody (HABA) response to AVX 470		4 weeks	Yes