Ignite Creation Date:
2024-05-05 @ 9:04 PM
Last Modification Date:
2024-10-26 @ 9:58 AM
Study NCT ID:
NCT00800930
Status:
COMPLETED
Last Update Posted:
2011-12-08
First Post:
2008-12-02
Brief Title:
Therapeutic Induction of Endogenous Antibiotics
Sponsor:
International Centre for Diarrhoeal Disease Research Bangladesh
Organization:
International Centre for Diarrhoeal Disease Research Bangladesh
Study Overview
Official Title:
Therapeutic Induction of Endogenous Antibiotics for Improved Recovery in Shigellosis
Status:
COMPLETED
Status Verified Date:
2008-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 eg 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 ie 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
Detailed Description:
Study design A double blind randomized clinical trial with subsequent follow-up
Study Subjects Adult male and female patients attending the Clinical Research and Service Center CRSC of ICDDRB and Matlab Hospital will be screened for participation in the study
Randomization
According to a computer-generated randomization list patients full filling the entry criteria will be randomized to either intervention group Pivmecellinam plus butyrate enema or control group Pivmecellinam plus normal saline enema Butyrate enema will contain 80 mmolL of butyrate in normal saline pH 72 Placebo enema will contain normal salinepH 72
Case management
After enrollment the patients will be admitted in the study ward of ICDDRB Dhaka and Matlab hospital A standard clinical history and clinical examination will be performed by one of the investigators or study physician All patients will receive Pivmecillinam 400 mg 8 hourly for 5 days The intervention group will receive butyrate enema 80 ml of 80 mM sodium butyrate 12 hourly for 72 hours while the placebo group will get 80 ml of normal saline 12 hourly for 72 hours All patients will receive the usual hospital food three times a day breakfast lunch and supper The patients will remain in the study ward for 5 days to enable identification of any relapse cases
Procedure for butyrate enema
Patients will be instructed to lie on a bed cholera cot in left lateral position A soft rectal catheter will be introduced by a nursephysician 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
Definition of clinical cure A patient will be defined as clinically cured if on day-3 no blood or mucus is observed in the stool there is 3 unformed stool in 24 hours and no fever oral temperature 375 C is recorded
Treatment failure A patient will be considered a treatment failure on day 3 when there is any one of the following features present 3 unformed stool in 24 hours presence of blood in any stool or presence of fever oral temperature 375 C
Collection of Samples
Patients will be requested to stay in the hospital for at least 5 days to facilitate disease monitoring and sampling On admission day patients will be enrolled after serological confirmation by slide agglutination test on the subsequent day ie day-1 stool specimens will be collected from each patient every day starting from the day of admission till 4 days after admission Rectal biopsy samples will be collected on the day of admission and 7 days after admission from patients enrolled in Dhaka hospital only Three mL blood will be collected after admission for measurement of C-reactive protein CRP that will be used as an indicator for monitoring magnitude of inflammation 1 mL blood from patients will be collected to measure CRP in serum on the 4th day of admission
Stool Fresh stool samples will be collected for routine microscopic examination for parasites or cysts and as well as RBC pus cells and macrophages Stool samples will also be tested for measuring bacterial countsload In brief 1 g of stool will be diluted in normal saline 110 vortex-mixed for 5 min followed by serial dilutions of 110 in normal saline and plated in MacConkey agar plates After overnight incubation at 37ºC bacterial cfu will be counted Fresh stool specimens will also be extracted as described earlier for measuring LL-37human beta-defensin 1 and 3 and proinflammatory cytokines interleukin-8 and 1beta by ELISA method
Rectal biopsy Rectal biopsy samples will be obtained from patients only in Dhaka Hospital
Study Subjects Adult male and female patients attending the Clinical Research and Service Center CRSC of ICDDRB and Matlab Hospital will be screened for participation in the study
Randomization
According to a computer-generated randomization list patients full filling the entry criteria will be randomized to either intervention group Pivmecellinam plus butyrate enema or control group Pivmecellinam plus normal saline enema Butyrate enema will contain 80 mmolL of butyrate in normal saline pH 72 Placebo enema will contain normal salinepH 72
Case management
After enrollment the patients will be admitted in the study ward of ICDDRB Dhaka and Matlab hospital A standard clinical history and clinical examination will be performed by one of the investigators or study physician All patients will receive Pivmecillinam 400 mg 8 hourly for 5 days The intervention group will receive butyrate enema 80 ml of 80 mM sodium butyrate 12 hourly for 72 hours while the placebo group will get 80 ml of normal saline 12 hourly for 72 hours All patients will receive the usual hospital food three times a day breakfast lunch and supper The patients will remain in the study ward for 5 days to enable identification of any relapse cases
Procedure for butyrate enema
Patients will be instructed to lie on a bed cholera cot in left lateral position A soft rectal catheter will be introduced by a nursephysician 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
Definition of clinical cure A patient will be defined as clinically cured if on day-3 no blood or mucus is observed in the stool there is 3 unformed stool in 24 hours and no fever oral temperature 375 C is recorded
Treatment failure A patient will be considered a treatment failure on day 3 when there is any one of the following features present 3 unformed stool in 24 hours presence of blood in any stool or presence of fever oral temperature 375 C
Collection of Samples
Patients will be requested to stay in the hospital for at least 5 days to facilitate disease monitoring and sampling On admission day patients will be enrolled after serological confirmation by slide agglutination test on the subsequent day ie day-1 stool specimens will be collected from each patient every day starting from the day of admission till 4 days after admission Rectal biopsy samples will be collected on the day of admission and 7 days after admission from patients enrolled in Dhaka hospital only Three mL blood will be collected after admission for measurement of C-reactive protein CRP that will be used as an indicator for monitoring magnitude of inflammation 1 mL blood from patients will be collected to measure CRP in serum on the 4th day of admission
Stool Fresh stool samples will be collected for routine microscopic examination for parasites or cysts and as well as RBC pus cells and macrophages Stool samples will also be tested for measuring bacterial countsload In brief 1 g of stool will be diluted in normal saline 110 vortex-mixed for 5 min followed by serial dilutions of 110 in normal saline and plated in MacConkey agar plates After overnight incubation at 37ºC bacterial cfu will be counted Fresh stool specimens will also be extracted as described earlier for measuring LL-37human beta-defensin 1 and 3 and proinflammatory cytokines interleukin-8 and 1beta by ELISA method
Rectal biopsy Rectal biopsy samples will be obtained from patients only in Dhaka Hospital
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None