Therapeutic Induction of Endogenous Antibiotics

NCT00800930 | Completed Phase 2 DMC

• 1 other identifier: 2004-031
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 2

Brief Summary

Shigellosis is one of the major causes of morbidity and mortality in many developing countries. The continued emergence of antibiotic resistant strains has complicated the treatment of shigellosis and has increased the cost of treatment markedly. Antimicrobial peptides are considered as endogenous antibiotic. A mixture of these antimicrobial peptides (LL-37 and beta-defensin) drenches the mucosal epithelial surfaces forming a barrier for invading microorganisms. Recently, we found that Shigella down-regulates the expression of LL-37 and beta-defensin 1 (HBD-1) in the colon of patients during acute shigellosis thereby facilitating bacterial invasion. Both LL-37 and HBD-1 could inhibit the growth of various microbes e.g. S. dysenteriae type 1, S. flexneri, and S. boydii. Our study indicated that bacterial DNA might be a potential mediator for the down- regulation in vitro. Down-regulation of LL-37 and HBD-1 was also seen in watery diarrhea caused by other pathogens. Thus, bacteria-mediated down-regulation of our front line defenses could be one strategy evolved by the pathogens to subvert this host-defense mechanism. gene encoding LL-37 in cultured epithelial cell lines were up-regulated when treated with butyrate; butyrate decreased the severity of Shigella infections in rabbit model. We could reproduce our findings from human i.e. downregulation of CAP-18 (the rabbit homologue to human LL-37) in colon epithelia after infection with Shigella flexneri. CAP-18 reappeared after treatment of the infected rabbits with sodium butyrate. Thus, the rabbit model demonstrated the proof of principal. In this study, we aim to assess the efficacy of sodium butyrate enema in reduction of clinical symptoms and / severity, reduction of inflammatory responses and induction of endogenous antibiotic activity in the rectum in adult patients with shigellosis.

Conditions

Shigellosis

Keywords

Shigellosis; sodium butyrate; antimicrobial peptides; LL-37; innate immunity; The aims are to assess efficacy of sodium butyrate enema in; marked improvement in clinical features; endoscopic findings; histological features; Induction of LL-37 in the rectum.

Outcome Measures

Primary Outcomes (1)

• The primary endpoints of the study is to assess the efficacy of sodium butyrate enema in adult patients with shigellosis in marked improvement in clinical, endoscopic and histological findings.

  4 years

Secondary Outcomes (1)

• To study the effect of sodium butyrate on the induction of endogenous antibiotic peptides in the rectum in adults with shigellosis.

  4 years

Study Arms (2)

1

ACTIVE COMPARATOR

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of butyrate solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

Biological: Sodium Butyrate

2

PLACEBO COMPARATOR

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of saline solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

Biological: Saline

Interventions

Sodium Butyrate BIOLOGICAL

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of butyrate solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

1

Saline BIOLOGICAL

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of saline solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

2

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• years of age
• duration of diarrhoea 0-4 days
• culture-confirmed Shigella spp (all Shigella spp) in stool on enrolment

You may not qualify if:

• who received antimicrobial treatment before attending the ICDDR,B hospital
• clinical symptoms of other concomitant infections (such as chronic respiratory infections, other concomitant gastrointestinal infections)

Sponsors & Collaborators

• International Centre for Diarrhoeal Disease Research, Bangladesh: lead
• Swedish International Development Cooperation Agency (SIDA): collaborator
• Karolinska Institutet: collaborator

Study Sites (2)

Dhaka Hospital & Matlab Hospital

Dhaka, 1212, Bangladesh

Location

ICDDR,B

Dhaka, 1212, Bangladesh

Location

Related Publications (2)

• Raqib R, Sarker P, Bergman P, Ara G, Lindh M, Sack DA, Nasirul Islam KM, Gudmundsson GH, Andersson J, Agerberth B. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9178-83. doi: 10.1073/pnas.0602888103. Epub 2006 Jun 1.

  PMID: 16740661 BACKGROUND

• Raqib R, Sarker P, Mily A, Alam NH, Arifuzzaman AS, Rekha RS, Andersson J, Gudmundsson GH, Cravioto A, Agerberth B. Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial. BMC Infect Dis. 2012 May 10;12:111. doi: 10.1186/1471-2334-12-111.

  PMID: 22574737 DERIVED

MeSH Terms

Conditions

Dysentery, Bacillary

Interventions

Butyric Acid; Sodium Chloride

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Dysentery; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Rubhana Raqib, Ph.D.

  International Centre for Diarrhoeal Disease Research, Bangladesh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2008
• First Posted: December 3, 2008
• Study Start: January 1, 2005
• Primary Completion: December 1, 2008
• Study Completion: January 1, 2009
• Last Updated: December 8, 2011

Record last verified: 2008-12

Locations

BA (2)