Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000450718
Ethics application status
Approved
Date submitted
15/05/2008
Date registered
19/04/2013
Date last updated
19/04/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
Butyrate as therapy for congenital chloride diarrhea
Scientific title
Effects of oral butyrate therapy on children with congenital chloride diarrhea
Secondary ID [1] 282209 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Congenital chloride diarrhea 3143 0
Condition category
Condition code
Human Genetics and Inherited Disorders 3302 3302 0 0
Other human genetics and inherited disorders
Oral and Gastrointestinal 289177 289177 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Diet and Nutrition 289178 289178 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We used a commercially available sodium butyrate formulation (SOBUTIR, Registered Trademark, Promefarm, Milan, Italy). Butyrate was administered orally at 100 mg/kg/day, divided in 2 doses, with a maximal dosage of 4 g/day, for 1 week. Number of tablets of sodium butyrate (1 gr/tablet) consumed by the child during the trial were reported in a specific form by the parents. A good compliance was considered the intake of at least 80% of the prescribed doses. Parents of the enrolled children were advised to avoid co-administration of other treatments, including anti-diarrheal drugs, antibiotics, probiotics or probiotics during the trial. Children continued their normal diet during the study period. During the entire length of the study, all CLD subjects were examined as outpatients and they had free access to the services of referred hospitals.
Intervention code [1] 2880 0
Treatment: Other
Comparator / control treatment
The same patients 1 week before the enrollment
Control group
Uncontrolled

Outcomes
Primary outcome [1] 4238 0
Fecal chloride and sodium concentrations.
Timepoint [1] 4238 0
Measured on the fecal sample collected in the last 3 days of baseline week and week of treatment. Data obtained during the week of treatment were compared with that of previuos baseline week.
Secondary outcome [1] 7084 0
Daily faecal volume. This outcome are collected in a specific graduated box the feces of 1 day and assessed by the child's parents
Timepoint [1] 7084 0
Measured daily for the entire duration of the trial. Data collected during the week of treatment were compared with that of previuos baseline week.
Secondary outcome [2] 7396 0
Number of bowel movements. These information are reported by the parents of enrolled children in a specific clinical chart.
Timepoint [2] 7396 0
Measured daily for the entire duration of the trial. Data collected during the week of treatment were compared with that of previuos baseline week.
Secondary outcome [3] 7397 0
Stool consistency (assessed using a scoring system: normal = 0, loose = 1, semi-liquid = 2, liquid =3). These information are reported by the parents of enrolled children in a clinical chart designed specifically for this trial.
Timepoint [3] 7397 0
Measured daily for the entire duration of the trial. Data collected during the week of treatment were compared with that of previuos baseline week.
Secondary outcome [4] 7398 0
Presence (value 1) or absence (value 0) of incontinence or urgency. These symptoms are reported by the parents of enrolled children in a clinical chart designed specifically for this trial
Timepoint [4] 7398 0
Measured daily for the entire duration of the trial. Data collected during the week of treatment were compared with that of previuos week.

Eligibility
Key inclusion criteria
All patients (age < 18 years) with diagnosis of congenital chloride diarrhea, will be considered eligible for the study.
Minimum age
1 Months
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Severe clinical conditions, concomitant presence of acute intestinal or extraintestinal infections, probiotics, non-steroideal anti-inflammatory drugs (NSAIDs), or antibiotics use in the last 4 weeks, chronic diseases (inflammatory bowel diseases, congenital motility disorders, food allergy, celiac disease, cystic fibrosis, immunodeficiency).

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This was an open trial on subjects with a confirmed diagnosis of CLD. The purposes and the modalities of the study were illustrated to the parents during the first visit (Visit 1), and an informed consent was obtained from parents or tutors of each enrolled patient. Baseline clinical and laboratory data were collected during the week before butyrate treatment, and were considered representative of the usual pattern of each enrolled patient. In particular, the parents of each patient were instructed to record daily in a specific clinical chart: number of bowel movements, fecal volume, stool consistency (using a scoring system: normal = 0, loose = 1, semi-liquid = 2, liquid =3), and presence of incontinence. At the end of the baseline week of observation, the clinical chart of the child was collected and the patient was re-evaluated during a new visit (Visit 2). A full clinical evaluation was performed and serum, fecal and urinary electrolytes concentrations; together with serum pH, renin and aldosterone values were determined, as previously described. Fecal electrolyte concentrations were measured on stool samples collected daily during the last 3 days of baseline observational period. The parents of each enrolled subject received a written prescription about the modalities of sodium butyrate administration for 1 week associated with oral NaCl/KCl supplementation, as previously described. In the last 3 days of treatment we collected daily a fecal sample to study the effect of butyrate on fecal Na+ and Cl- concentration. At the end of the week of treatment with butyrate, the patients were re-evaluated (Visit 3), and serum, urinary and fecal electrolyte concentrations were measured again. Primary outcome of the study is the reduction of Cl- and Na+ fecal losses induced by butyrate therapy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The Kolmogorov-Smirnov test was used to determine whether variables were normally distributed. The chi-square test was applied for categorical variables, and for continuous variables, differences between groups were analyzed by Mann- Whitney U test, and Kruskal-Wallis H test. A multivariate analysis was performed to evaluate if the effects of butyrate may depend by clinical or genetic factors. All analyses were conducted on an intention-to-treat (ITT) basis. Statistical analysis was carried out by the SPSS software for Windows 16.0 and by StatDirect 1.7.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2008
Actual
12/11/2009
Date of last participant enrolment
Anticipated
Actual
6/12/2010
Date of last data collection
Anticipated
Actual
Sample size
Target
7
Accrual to date
Final
Recruitment outside Australia
Country [1] 965 0
Italy
State/province [1] 965 0
Naples

Funding & Sponsors
Funding source category [1] 3378 0
University
Name [1] 3378 0
University of Naples Federico II
Country [1] 3378 0
Italy
Primary sponsor type
University
Name
Department of Pediatrics, University of Naples Federico II
Address
5, via Pansini, Naples, Italy, 80131
Country
Italy
Secondary sponsor category [1] 285834 0
None
Name [1] 285834 0
Address [1] 285834 0
Country [1] 285834 0
Other collaborator category [1] 286 0
University
Name [1] 286 0
Department of Biothecnology University of Naples Federico II
Address [1] 286 0
via Pansini 5, 80131, Naples
Country [1] 286 0
Italy
Other collaborator category [2] 287 0
University
Name [2] 287 0
University of Naples, Genetic Enginery Research Center (CEINGE)
Address [2] 287 0
5, via Pansini, Naples, Italy, 80131
Country [2] 287 0
Italy

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5404 0
University of Naples Federico II
Ethics committee address [1] 5404 0
5, via Pansini, Naples, Italy, 80131
Ethics committee country [1] 5404 0
Italy
Date submitted for ethics approval [1] 5404 0
01/10/2007
Approval date [1] 5404 0
19/11/2007
Ethics approval number [1] 5404 0
222/07

Summary
Brief summary
Congenital chloride diarrhea (CLD) is an inherited disorder characterized due to mutations in the SLC26A3 gene. The clinical picture of CLD patients range from severe neonatal diarrhea, with high risk of life threatening hypoelectrolytemia and dehydration events, to a relatively mild chronic form. In patients with CLD, oral supplementation therapy with a combination of chloride salts (NaCl and KCl) is essential in preventing episodes of dehydration that could result in mental impairment and renal dysfunctions. Unfortunately, this therapy is unable to limit the severity of diarrhea.
Dietary fibres are fermented by intestinal bacteria microflora into short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. The role of the SCFA has been increasingly recognized for the management of diarrheal diseases. Butyrate is able to exert a powerful pro-absorptive stimulus on intestinal salts. In a child affected by CLD, we demonstrated the therapeutic efficacy of oral butyrate, showing a progressive reduction to normal values in the number of bowel movements and stool volume, an improvement in stool consistency, and a reduction of fecal incontinence episodes. The aim of this study is to evaluated the therapeutic effect of butyrate in children affected by CLD.
Trial website
Trial related presentations / publications
1.Passariello A, Baldassarre M, Bernardo I, Cipolla D, Longo R, Cimadamore N, Ruotolo S, Terrin G, Cirillo P, Cassata N, Berni Canani R. Neonatal diarrhea: a multicenter study. J Pediatr Gastroenterol Nutr 2004; 39:S250.
2.Berni Canani R, Cirillo P, Terrin G. Chronic and intractabile diarrea. In: Guandalini S. Ed. Essential Pediatric Gastroenterology Hepatology, and Nutrition. Mc Graw-Hill Mediacla Publishing Division Chicago 2005: 25-47.
3.Makela S, Kere J, Holmberg C, Hoglund P. SLC26A3 mutations in congenital chloride diarrhea. Hum Mutat. 2002;20(6):425-38.
4.Hoglund P, Haila S, Socha J, Tomaszewski L, Saarialho-Kere U, Karjalainen-Lindsberg ML, Airola K, Holmberg C, de la Chapelle A, Kere J. Mutations of the down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nature Genet 1996;14:316-319.
5.Hoglund P, Auranen M, Socha J, Popinska K, Nazer H, Rajaram U, Al Sanie A, Al-Ghanim M, Holmberg C, de la Chapelle A, Kere J. Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland and Saudi Arabia and Kuwait. Am J Hum Genet 1998;63:760-768.
6.Hoglund P, Sormaala M, Haila S, Socha J, Rajaram U, Scheurlen W, Sinaasappel M, de Jonge H, Holmberg C, Yoshikawa H,Kere J. Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea. Hum Mutat 2001;18:233-242.
7.Nguyen TD, Kim US, Perrine SP. Novel short chain fatty acids restore chloride secretion in cystic fibrosis. Biochem Biophys Res Commun 2006;342:245-252
8.Berni Canani R, Terrin G, Cirillo P, Castaldo G, Salvatore F, Cardillo G, Coruzzo A, Troncone R. Butyrate as an effective treatment of congenital chloride diarrhea. Gastroenterology. 2004; 127(2):630-4.
9.Makela S, Kere J, Holmberg C. SLC26A3 mutations in congenital chloride diarrhea Hum Mutat 2002;20:425-438.
10.Terrin G, Castaldo G, Cardillo G, Salvatore F, Troncone R, Berni Canani R. Gastroenterology 2006;130 S2:A374.
11.Gray MA. Bicarbonate secretion: it takes two to tango. Nat Cell Biol 2004;6: 292-294.
12.Kunzelmann K and Mall M. Electrolyte transport in the mammalian colon: mechanisms and implication for disease. Physiol Rev 2002;82:245-289.
13.Field M. Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest 2003;111:931-943.
Public notes

Contacts
Principal investigator
Name 28585 0
Prof Roberto Berni Canani
Address 28585 0
Department of Pediatrics
University of Naples Federico II
via Pansini 5
80131 Naples
Country 28585 0
Italy
Phone 28585 0
+390817462680
Fax 28585 0
Email 28585 0
[email protected]
Contact person for public queries
Name 11742 0
Prof Roberto Berni Canani
Address 11742 0
Department of Pediatrics
University of Naples Federico II
via Pansini 5
80131, Naples
Country 11742 0
Italy
Phone 11742 0
+39 0817462680
Fax 11742 0
+39 0815451278
Email 11742 0
[email protected]
Contact person for scientific queries
Name 2670 0
Prof Roberto Berni Canani
Address 2670 0
Department of Pediatrics
University of Naples Federico II
via Pansini 5
80131 Naples
Country 2670 0
Italy
Phone 2670 0
+39 0817462680
Fax 2670 0
+39 0815451278
Email 2670 0
[email protected]

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