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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]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Congenital chloride diarrhea

Condition category

Condition code

Human Genetics and Inherited Disorders

Other human genetics and inherited disorders

Oral and Gastrointestinal

Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Diet and Nutrition

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]

Treatment: Other

Comparator / control treatment

The same patients 1 week before the enrollment

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Fecal chloride and sodium concentrations.

Timepoint [1]

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]

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]

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]

Number of bowel movements. These information are reported by the parents of enrolled children in a specific clinical chart.

Timepoint [2]

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]

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]

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]

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]

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?

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

Italy

State/province [1]

Naples

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Naples Federico II

Address [1]

5, via Pansini, Naples, Italy, 80131

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

University

Name [1]

Department of Biothecnology University of Naples Federico II

Address [1]

via Pansini 5, 80131, Naples

Country [1]

Italy

Other collaborator category [2]

University

Name [2]

University of Naples, Genetic Enginery Research Center (CEINGE)

Address [2]

5, via Pansini, Naples, Italy, 80131

Country [2]

Italy

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

University of Naples Federico II

Ethics committee address [1]

5, via Pansini, Naples, Italy, 80131

Ethics committee country [1]

Italy

Date submitted for ethics approval [1]

01/10/2007

Approval date [1]

19/11/2007

Ethics approval number [1]

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

Prof Roberto Berni Canani

Address

Department of Pediatrics
University of Naples Federico II
via Pansini 5
80131 Naples

Country

Italy

Phone

+390817462680

Fax

[email protected]

Contact person for public queries

Name

Roberto Berni Canani

Address

Department of Pediatrics
University of Naples Federico II
via Pansini 5
80131, Naples

Country

Italy

Phone

+39 0817462680

Fax

+39 0815451278

[email protected]

Contact person for scientific queries

Name

Roberto Berni Canani

Address

Department of Pediatrics
University of Naples Federico II
via Pansini 5
80131 Naples

Country

Italy

Phone

+39 0817462680

Fax

+39 0815451278

[email protected]

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