Probiotics in Cystic Fibrosis

Effects of LGG Administration in Children With Cystic Fibrosis: A Randomized Controlled Trial

Cystic fibrosis (CF) is a complex systemic disease that mainly involves the respiratory and gastrointestinal (GI) tracts. The polymicrobial community composition of respiratory and GI tracts is influenced by both genetic and environmental factors. Children with CF may harbor an abnormal intestinal microflora, because of altered cystic fibrosis transmembrane conductance regulator (CFTR) function and heavy drug load (antibiotics, pancreatic enzymes and acid suppressors). The investigators have previously demonstrated that intestinal inflammation is highly frequent in CF children, being a major feature of intestinal involvement. In addition, specific probiotics significantly improved airway and GI inflammation in a preliminary trial. The investigators aim to characterize intestinal and respiratory microflora in CF patients and to investigate the effects of daily Lactobacillus GG (LGG) supplementation on both GI and airway microflora and the eventual relationship between probiotic assumption and clinical and inflammation markers. The investigators aim is to eventually improve the quality of life of CF patients, who often suffer from intestinal and respiratory progressive disease, through a non invasive intervention consisting in the supplementation of probiotic bacteria.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Dietary supplement: Lactobacillus rhamnosus GG; Dietary supplement: placebo

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Florence, Italy
    • - Department of Paediatric Medicine, CF Center, "A. Meyer" Children's Hospital
  • Messina, Italy
    • Dipartimento di Pediatria - Università Di Messina
  • Milano, Italy
    • Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena
  • Napoli, Italy
    • Università degli Studi di Napoli "Federico II"
  • Rome, Italy
    • Ospedale "Bambino Gesù" - Roma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. A confirmed diagnosis of CF documented by sweat chloride test over 60 mmol/L and confirmed by genotype analysis with the presence of F508del/F508del or F508del/other
2. Boys and girls between 2 and 16 years of age
3. Clinical stability at enrolment, defined as no clinical evidence of acute exacerbation, no modifications in the therapeutic regimen and no hospitalization in the last 2 weeks
4. Pancreatic insufficiency
5. Basal Forced Expiratory Volume 1 second above 50% of predicted value

Exclusion Criteria:

1. Colonization of respiratory tract with Burkholderia cepacia spp.
2. Steroid therapy within one month before enrolment
3. Pregnancy and fertile women taking oral contraceptives
4. Parenteral or oral antibiotics therapy within 2 weeks before enrolment
5. Regular assumption of probiotics
6. Regular assumption of azythromycin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Probiotics; Capsules containing lyophilized 6x10^9 Colony Forming Units (CFU)/die of Lactobacillus rhamnosus GG (LGG)	Dietary supplement: Lactobacillus rhamnosus GG; Capsules containing lyophilized 6x10^9 Colony Forming Units (CFU)/die LGG, (60mg) maltodextrin (163 mg), gelatine capsule (75 mg), magnesium stearate (2 mg) 1 cps/die for 12 months; Other Names: LGG
PLACEBO_COMPARATOR: Placebo; Capsules containing maltodextrin	Dietary supplement: placebo; Capsules containing maltodextrin (163 mg), gelatine capsule (75 mg), magnesium stearate (2 mg) 1 cps/die for 12 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the incidence of pulmonary exacerbations from baseline to 12 months of treatment	The incidence of pulmonary exacerbation is assessed every six months. First evaluation from baseline to 6 months of observation. Second evaluation from randomization ( placebo/LGG) to 6 months of treatment and third evaluation after 12 months of treatment	every six months up to 18 months
Change of intestinal inflammation from baseline to 12 months of treatment	Assessment of intestinal inflammation is performed four times. First time at enrollment, second time at the end of six months of observation. Third time after six months of treatment and fourth time after 12 months of treatment.	every six months up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the incidence of hospital admission from baseline to 12 months of treatment	The incidence of hospital admission is assessed every six months. First evaluation from baseline to 6 months of observation. Second evaluation from randomization ( placebo/LGG) to 6 months of treatment and third evaluation after 12 months of treatment	every six month up to 18 months
change in pulmonary function from baseline to 12 months of treatment (measured by Forced Expiratory Volume 1 sec (FEV1))	Assessment of pulmonary function is performed four times. First time at enrollment, second time at the end of six months of observation. Third time after six months of treatment and fourth time after 12 months of treatment.	every six months up to 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the incidence of abdominal pain episodes from baseline to 12 months of treatment	The incidence of abdominal pain episodes is assessed every six months. First evaluation from baseline to 6 months of observation. Second evaluation from randomization ( placebo/LGG) to 6 months of treatment and third evaluation after 12 months of treatment	every six months up to 18 months
Change in systemic inflammation from baseline to 12 months of treatment	Assessment of intestinal microflora composition is performed 2 times. First time at randomization (placebo/LGG), second time at the end of 12 months of treatment.	At baseline and after 12 months of treatment
Change of intestinal microflora composition from baseline to 12 months of treatment	Assessment of intestinal microflora composition is performed 2 times. First time at randomization (placebo/LGG), second time at the end of 12 months of treatment.	baseline and 12 months after treatment

Collaborators and Investigators

• Sponsor: Federico II University

Publications and helpful links

General Publications

• Bruzzese E, Raia V, Spagnuolo MI, Volpicelli M, De Marco G, Maiuri L, Guarino A. Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis: a pilot study. Clin Nutr. 2007 Jun;26(3):322-8. doi: 10.1016/j.clnu.2007.01.004. Epub 2007 Mar 13.
• Bruzzese E, Raia V, Gaudiello G, Polito G, Buccigrossi V, Formicola V, Guarino A. Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration. Aliment Pharmacol Ther. 2004 Oct 1;20(7):813-9. doi: 10.1111/j.1365-2036.2004.02174.x.
• Raia V, Maiuri L, de Ritis G, de Vizia B, Vacca L, Conte R, Auricchio S, Londei M. Evidence of chronic inflammation in morphologically normal small intestine of cystic fibrosis patients. Pediatr Res. 2000 Mar;47(3):344-50. doi: 10.1203/00006450-200003000-00010.
• Lucidi V, Alghisi F, Raia V, Russo B, Valmarana L, Valmarana R, Coruzzo A, Beschi S, Dester S, Rinaldi D, Maglieri M, Guidotti ML, Ravaioli E, Pesola M, De Alessandri A, Padoan R, Grynzich L, Ratclif L, Repetto T, Ambroni M, Provenzano E, Tozzi AE, Colombo C. Growth assessment of paediatric patients with CF comparing different auxologic indicators: A multicentre Italian study. J Pediatr Gastroenterol Nutr. 2009 Sep;49(3):335-42. doi: 10.1097/MPG.0b013e31818f0a39.
• Miragoli F, Federici S, Ferrari S, Minuti A, Rebecchi A, Bruzzese E, Buccigrossi V, Guarino A, Callegari ML. Impact of cystic fibrosis disease on archaea and bacteria composition of gut microbiota. FEMS Microbiol Ecol. 2017 Feb;93(2):fiw230. doi: 10.1093/femsec/fiw230. Epub 2016 Nov 2.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: September 23, 2013
• First Submitted That Met QC Criteria: September 30, 2013
• First Posted (ESTIMATE): October 8, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): September 23, 2015
• Last Update Submitted That Met QC Criteria: September 22, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Inflammation; Intestinal microbiota; Pulmonary exacerbation
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: CF001; 2009-011289-27 (EUDRACT_NUMBER)