Methods

Trial design: RCT.

Trial grouping: cross‐over, without a washout period.

Randomisation method: randomisation was constructed using the random numbers table with a block design for groups of 10 participants.

Participants

Inclusion criteria

• Children with CF diagnosed by an elevated sweat chloride concentration.

• Moderate/severe disease evaluated according to the criteria of the CF Foundation.

• Chronic colonisation with P aeruginosa defined as a positive sputum for at least 6 months in at least 3 consecutive cultures.

• Pancreatic insufficiency as judged by steatorrhea and clinical symptoms.

Exclusion criteria

• Clinical instability (clinical stability was defined as the absence of substantial, acute onset clinical problems that could affect the outcome measures included in the clinical protocol, at the time of enrolment, shift of treatment and/or exit from treatment).

Baseline characteristics

• Participants: total n = 38.

• Age, mean (SD) years: 13.2 (4.2).

• Gender distribution, number (%) males: 16 (42.1%).

• F508del / F508del, number (%): 16 (42.1%).

• Pancreatic insufficient, number (%): 38 (100%).

Interventions

Probiotic

• Preparation: Lactobacillus GG (6 x 10⁹ CFU/day) dissolved in ORS.

• Dose (probiotic): 6 x 10⁹CFU/day.

• Frequency of administration: daily.

• Duration: 6 months.

Placebo

• Preparation: ORS.

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 6 months.

Outcomes

Primary outcome measures

• Number of pulmonary exacerbations (defined using CF Foundation criteria).

• Duration (days) of antibiotic therapy for pulmonary exacerbations.

• Number and duration (days) of hospital admissions for pulmonary exacerbations.

• Route of administration of antibiotics (oral vs intravenous).

• Lung function (FEV₁ % predicted), mean change from baseline.

• Weight (kg), mean change from baseline.

• BMI (kg/m²), mean change from baseline.

• Serum immunoglobulin concentrations: IgA, IgG and IgM (mg/dL), mean change from baseline

Secondary outcome measures

• Adverse events including serious adverse reactions, adverse reactions and mortality.

Time points for measurements: baseline 6 months for each period (baseline, 6 months, 7 months, 13 months).

Length of follow‐up: 56 weeks.

Identification

Country: Italy.

Setting: Department of Pediatrics, University of Naples "Federico II".

Author's name: Alfredo Guarino.

Institution: Department of Pediatrics, University of Naples "Federico II".

Email: [email protected].

Address: Department of Pediatrics, University of Naples "Federico II", Via S. Pansini 5, 80131 Naples, Italy.

Funding Source

Fondazione per la ricerca sulla fibrosi cistica (grant).

Declaration of Interest Among the Primary Researchers

No conflicts of interest exists for any author.

Notes

Pretreatment: Group A (started on Lactobacillus GG first then ORS) had higher mean value of FEV1 %, P < 0.05

Population: in text age range (5 ‐ 23 years) does not match table 1 (5 ‐ 18 years); number of males in text (16) does not match table 1 (17), mean FEV1 % predicted = 63.57 (19.5) in Group A and mean FEV₁ % predicted = 45.37 (13.3) in Group B.
Outcomes: weight mean (SD) 1.98 (1.93) kg in probiotic group vs 0.78 (1.97) kg in placebo group for first phase; MD 1.2 (95% CI 0.08 ‐ 2.48).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomisation was constructed using the random numbers table with a block design for groups of ten patients."

Judgement comment: block design for groups of 10 participants used ‐ methods to prevent selection bias not taken as stringent inclusion criteria taken to limit baseline group differences.

Allocation concealment (selection bias)

Unclear risk

Judgement comment: unclear about allocation concealment mechanism.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "LGG or ORS were assumed, blindly, in a single daily dose by the patients."

Judgement comment: participants blinded. Investigators (except outcome assessor) not blinded, however, this is unlikely to affect objective outcome measures.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The outcome measures of efficacy were recorded by one of the investigators who was unaware about the administration of LGG/ORS."

Judgement comment: outcome assessor blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "Clinical stability was defined as the absence of substantial, acute onset clinical problems that could affect the outcome measures included in the clinical protocol, at the time of enrolment, shift of treatment and/or exit from treatment."

Quote: "One of the 5 patients who did not complete the study was unable to receive probiotics because of vomiting, and whereas the other 4 were clinically unstable at the end of probiotic or ORS administration."

Quote: "Thirty‐eight of the 43 patients enrolled, completed the study"

Judgement comment: 4 clinically unstable participants were not analysed, this may skew outcome measures.

Selective reporting (reporting bias)

Low risk

Judgement comment: data not given for not significant results, e.g. mean duration of hospital stay per pulmonary episode, mean duration of pulmonary exacerbations, otherwise reported on everything in methods ‐ no protocol available.

Other bias

Low risk

Judgement comment: Fondazione Ricerca Fibrosi Cistica funding. No conflicts declared.

Methods

Trial design: RCT.

Trial grouping: parallel groups.

Randomisation method: not specified ("generated by a statistician not involved in patient management").

Participants

Inclusion criteria

• 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.

• Boys and girls between 2 and 18 years of age.

• Clinical stability at enrolment, defined as no clinical evidence of acute exacerbation, no modifications in the therapeutic regimen and no hospitalisation in the last 2 weeks.

• Pancreatic insufficiency.

• Baseline FEV₁ above 50% of predicted value.

Exclusion criteria

• Colonization of respiratory tract with Burkholderia cepacia spp.

• Steroid therapy within 1 month before enrolment.

• Pregnancy and fertile women taking oral contraceptives.

• Parenteral or oral antibiotics therapy within 2 weeks before enrolment.

• Regular assumption of probiotics.

• Regular assumption of azithromycin.

Baseline characteristics

• Participants: total n = 22 (probiotic group n = 10; placebo group n = 12).

• Age, median (range; years): 7 (2 ‐ 9).

• Gender distribution, number (%) males: 13 (59.1%).

• F508del / F508del, number (%): 12 (54.5%).

Interventions

Probiotic

• Preparation: Lactobacillus GG (60 mg), maltodextrin (163 mg), gelatin capsule (75 mg) and magnesium stearate (2 mg).

• Dose (probiotic): 6 x 10⁹ CFU.

• Frequency of administration: daily.

• Duration: 1 month.

Placebo

• Preparation: maltodextrin (223 mg), gelatin capsule (75 mg), and magnesium stearate (2 mg).

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 1 month.

Outcomes

Primary outcome measures

• FISH analysis for bacterial loads of Bacteroides, F prauznitzii and E rectale (×10¹⁰/mL), mean change from baseline.

• Faecal calprotectin (µg/g), mean change from baseline.

Time points for measurements: baseline and 1 month.

Length of follow‐up: 4 weeks.

Identification

Country: Italy

Setting: Department of Pediatrics, University of Naples "Federico II".

Author's name: Alfredo Guarino.

Institution: Department of Translational Medical Science, Section of Pediatrics, University Federico II, Naples, Italy.

Email: [email protected].

Address: Department of Translational Medical Science, Section of Pediatrics University of Naples Federico II Naples, Italy.

Funding Source

Grants from the Cystic Fibrosis Foundation and Therapeutics (GUARIN10A0/2009) and the Fondazione Italiana Ricerca Fibrosis Cistica (FC 23/2009).

Declaration of Interest Among the Primary Researchers

The authors declared that no competing interests existed.

Notes

Baseline calprotectin, mean (SD): LGG group 164 (70), placebo group 251 (174).

This trial recruited healthy controls (without CF) to act as a reference for normal (e.g. inflammatory markers): data from these healthy participants are not included in the review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The randomisation protocol was generated by a statistician not involved in patient management."

Judgement comment: not clear what type of randomisation process was used.

Allocation concealment (selection bias)

Unclear risk

Quote: "Patients were randomly assigned to the treatment or placebo arms."

Judgement comment: not clear who performed the allocation and if concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind randomized clinical trial"

Quote: "LGG and placebo capsules were identical in appearance, taste, and colour, and only a numeric code differentiated the two formulations."

Quote: "LGG and placebo formulations were masked and coded appropriately to ensure blindness."

Judgement comment: protocol confirms blinding of participants, care providers and investigators.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: unclear if outcome assessors were blinded but outcome measures are objective.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: 25 participants were assessed for eligibility. All 22 participants randomised were analysed.

Selective reporting (reporting bias)

High risk

Quote: "Children with CF who were treated with LGG showed a significant decrease in fecal CLP concentration as compared with those treated with placebo (164 +/‐ 70 vs. 78 +/‐ 54 µg/g, P<0.05; 251 +/‐ 174 vs. 176 +/‐ 125 µg/g, P = 0.3, respectively)."

Judgement comment: comparison within groups but not between groups. Adverse events not reported.

Other bias

Low risk

Judgement comment: competitive grant funding with no influence on trial design and nil competing interests disclosed.

Methods

Trial design: RCT.

Trial grouping: parallel group.

Randomisation method: Pocock‐Simon covariate‐adaptive randomisation scheme was adopted with a bias parameter equal to 2/3. The stratification variables considered were sex (2 levels) and age (3 levels). Randomisation was centralised.

Participants

Inclusion criteria

• 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.

• Boys and girls between 2 and 16 years of age.

• Clinical stability at enrolment, defined as no clinical evidence of acute exacerbation, no modifications in the therapeutic regimen and no hospitalisation in the last 2 weeks.

• Pancreatic insufficiency (faecal elastase 200 μ/g).

• Baseline FEV₁ % predicted over 50%.

Exclusion criteria

• Colonization of respiratory tract with Burkholderia cepacia spp.

• Steroid therapy within 1 month before enrolment.

• Pregnancy and fertile women taking oral contraceptives.

• Parenteral or oral antibiotics therapy within 2 weeks before enrolment.

• Regular assumption of probiotics.

• Regular assumption of azithromycin.

Pretreatment: no overt group differences between those on probiotic and those on placebo.

Baseline characteristics

Overall

• Participants: total n = 81.

• Age, range years: 2 ‐ 17.

• Gender distribution, number (%) males: 41 (50.6%).

• F508del / F508del, number (%): 36 (44%).

• Pancreatic insufficient, number (%): 81 (100%).

Probiotic

• Participants: n = 41.

• Age, median (range) years: 8.7 (2.4 ‐ 16.8).

• Gender distribution, number (%) males: 21 (52.1%).

• F508del / F508del, number (%): 19 (46.3%).

• Pancreatic insufficient, number (%): 41 (100%).

• BMI median (range) kg/m²: 16.3 (14.5 ‐ 24.6).

• FEV₁ % predicted median (range): 94.7% (57% ‐ 129.4%).

• MMEF 25 ‐ 75%, median (range) %: 86.2% (32.5% ‐ 161.9%).

Placebo

• Participants: n = 40.

• Age, median (range) years: 7.3 (2.1 ‐ 15.7).

• Gender distribution, number (%) males: 20 (50%).

• F508del / F508del, number (%): 17 (42.5%).

• Pancreatic insufficient, number (%): 40 (100%).

• BMI median (range) kg/m²: 17.1 (13.5 ‐ 26.7).

• FEV₁ % predicted median (range): 97% (61% ‐ 151%).

• MMEF 25‐75%, median (range) %: 73% (35.4% ‐ 140.5%).

Interventions

Probiotic

• Preparation: Lactobacillus GG 60 mg (6x10⁹ CFU/day) capsule, maltodextrin (163 mg), gelatin capsule (75 mg), magnesium stearate (2 mg).

• Dose (probiotic): 6x10⁹ CFU/day (1 capsule).

• Frequency of administration: daily.

• Duration: 12 months.

Placebo

• Preparation: maltodextrin (163 mg) capsule, gelatin capsule (75 mg), magnesium stearate (2 mg)

• Dose (probiotic): 0 (1 capsule).

• Frequency of administration: daily.

• Duration: 12 months.

Outcomes

Primary outcome measures

• Proportion of participants with at least 1 pulmonary exacerbation during the intervention period (12 months).

• Proportion of participants with at least 1 hospitalisation during the intervention period (12 months).

Secondary outcome measures

• Number of pulmonary exacerbations (defined as an acute event with respiratory symptoms requiring antibiotic therapy (oral/parenteral) for at least 7 days as defined by the specialist at the reference centre).

• Duration (days) of antibiotic therapy for pulmonary exacerbations.

• Number of hospital admissions.

• Lung function (FEV₁ % predicted and MMEF 25‐75%), mean change from baseline.

• BMI (kg/m²), mean change from baseline.

Time points for measurements: ‐ 6 months (pre‐allocation), 0 months (baseline), 6 months (midway), 12 months (completion).

Length of follow‐up: 52 weeks.

Identification

Country: Italy.

Setting: multicentre study with 5 CF Regional Centres.

Author's name: Alfredo Guarino.

Institution: Department of Translational Medicine, Section of Paediatrics, University of Naples.

Email: [email protected].

Address: Department of Translational Medicine, Section of Pediatrics, University of Naples“Federico II”, Via Pansini 5, 80131 Naples, Italy.

Funding Source

Grant funding from the Cystic Fibrosis Foundation and Therapeutics (GUARIN10A0).

Probiotic and placebo was supplied by DICOFARM.

Declaration of Interest Among the Primary Researchers

Alfredo Guarino received research grant funding from DICOFARM not related to the present trial.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Pocock‐Simon covariate‐adaptive randomisation scheme was adopted".

Judgement comment: appropriate randomisation scheme.

Allocation concealment (selection bias)

Low risk

Quote: "Randomisation was centralised."

Quote: "randomised"

Judgement comment: appropriate allocation concealment using random sequence.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "LGG and placebo preparations were identical in appearance, taste, and colour to ensure blindness, the numeric code being the only distinctive feature."

Judgement comment: double‐blind study (participants and investigators) confirmed in study study protocol. Identical probiotic and placebo formulations.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Judgement comment: blinding of outcome assessors was not described.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: 81 participants randomised, 4 (5%) lost to follow‐up (3 probiotic group and 1 control group).

Quote: "Respiratory function tests were performed only in compliant subjects with CF in accordance to the protocol."

Judgement comment: unclear how many participants were included in the FEV₁ and MMEF analyses.

Selective reporting (reporting bias)

High risk

Quote: "Intestinal inflammation"

Judgement comment: as outlined in protocol, intestinal inflammation, abdominal pain and intestinal microbiota not reported in study. Adverse events not reported.

Other bias

Low risk

Judgement comment: funding sources and Dicofarm did not appear to influence the study design, conduct or results.

Methods

Trial design: RCT.

Trial grouping: parallel group.

Randomisation method: block randomisation with strata for age and gender.

Participants

Inclusion criteria

CF group

• Children and adolescents aged 1 year to 16 years.

• Diagnosed with CF (chloride sweat test ≥ 60 mmol/L).

• Clinically stable for at least 30 days prior to the data collection process.

Exclusion criteria

• Participants with fever, trauma, inflammatory diseases (asthma, inflammatory bowel disease, rheumatic disease), psychiatric, degenerative, cardiovascular, diabetes, glucose intolerance, renal failure, primary or secondary immunodeficiency.

• Participants being treated with antibiotics at baseline; hormones, non‐hormonal anti‐inflammatory drugs, immunosuppressants and antihistamines, up to 30 days prior to data collection.

• Participants experiencing a pulmonary exacerbation.

Pretreatment: placebo group had significantly worse nutritional status and inflammatory markers at baseline compared with intervention group.

Baseline characteristics

Overall

• Participants: n = 41.

• Gender distribution, number (%) males: 22 (53.7%).

Probiotic

• Participants: n = 22.

• Age, mean (SD) years: 9.6 (2.8).

• Gender distribution, number (%) males: 12 (54.5%).

• FEV₁ % predicted, median (IQR): 88.9% (58.6% ‐ 97.0%).

Placebo

• Participants: n = 19.

• Age, mean (SD) years: 10.7 (2.5).

• Gender distribution, number (%) males: 10 (52.6%).

• FEV₁ % predicted, median (IQR): 74.4% (51.2% ‐ 97.0%)

Interventions

Probiotic

• Preparation: FOS (5.5 g), L paracasei (10⁸ ‐ 10⁹ CFU/day), L rhamnosus (10⁸ ‐ 10⁹ CFU/day), L acidophilus (10⁸ ‐ 10⁹ CFU/day), and B lactis (10⁸ ‐ 10⁹ CFU/day) as a powder.

• Dose (probiotic): 4x 10⁸ to 4x 10⁹ CFU (108 – 109 CFU/day each strain) (1 sachet).

• Frequency of administration: daily.

• Duration: 90 days.

Placebo

• Preparation: maltodextrin (6 g).

• Dose (probiotic): 0 (1 sachet).

• Frequency of administration: daily.

• Duration: 90 days.

Outcomes

Primary outcome measures

• Lung function (FEV₁ % predicted), mean change from baseline.

• Weight (kg), mean change from baseline.

• Height (kg), mean change from baseline.

• BMI (kg/m²), mean change from baseline.

• Serum inflammatory marker concentrations: IL‐12, TNF‐ α, IL‐10, IL‐6, IL‐1β, IL‐8, MPO and NOx, mean change from baseline.

Time points for measurements: 0 days (baseline), 90 days (completion).

Length of follow‐up: 13 weeks.

Identification

Country: Brasil.

Setting: Joana de Gusmão Children’s Hospital.

Author's name: Emilia Addison Machado Moreira.

Institution: Department of Nutrition, Graduate Program in Nutrition, Federal University of Santa Catarina, Florianópolis, Brazil.

Email: [email protected].

Funding Source

National Council for Scientific and Technological Development. UNIEDU‐Santa Catarina and the CAPES. Farmoquímica.

Declaration of Interest Among the Primary Researchers

No conflicts declared.

Notes

This trial recruited healthy children and adolescents aged between 1 and 16 years without CF to act as a reference for normal (e.g. inflammatory markers). These children were clinically stable for at least 30 days prior to the data collection process. Data from these healthy participants are not included in the review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "a block randomisation process and stratified by sex and age".

Judgement comment: appropriate randomisation scheme.

Allocation concealment (selection bias)

Unclear risk

Quote: "The non‐probabilistic, convenience sample was composed of 72 children and adolescents allocated".

Judgement comment: allocation concealment mechanism not specified.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "randomized, placebo‐controlled, double‐blind trial"

Judgement comment: participants and personnel blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judegement comment: assessor blinding not specified, however double‐blind study and all outcomes of interest objective.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Five sets of imputed data were created".

Judegement comment: 5 sets of missing data; intention‐to‐treat analysis including a principal analysis using multiple imputations.

Selective reporting (reporting bias)

High risk

Judegement comment: CRP, lymphocytes and monocytes reported at baseline but not completion. Not all markers in protocol have been measured or recorded. This includes: serum IL‐17A, TGF‐beta, INF‐gamma, faecal calprotectin, intestinal microbiota and handshaking force. Adverse events not reported.

Other bias

Low risk

Quote: "The authors declare that they have no competing interests."

Judegement comment: no conflicts for authors., competitive grant funding, synbiotic donated.

Methods

Trial design: RCT.

Trial grouping: parallel group.

Randomisation method: randomisation between 2 probiotic preparations, method not specified.

Participants

Inclusion criteria

• Participants with CF.

Exclusion criteria

• Not specified.

Baseline characteristics

• Participants: n = 40.

• Age, range years: 4 ‐ 44.

• Gender distribution, number (%) males: 22 (55%).

Interventions

Probiotic 1

• Preparation: CasenBiotic (CasenFleet) 100 million (10⁸ CFU/day), L reuteri Protectis (DSM 17938), sweeteners (isomaltose (E‐953), xylitol (E‐967)), calcium stearate, palmitic acid, citric acid, strawberry aroma as a capsule.

• Dose (probiotic): 1 x 10⁸ CFU/day (1 capsule).

• Frequency of administration: daily.

• Duration: 6 months.

Probiotic 2

• Preparation: VLS3 (Faes Farma) 450 million, B breve, B longum, B infantis, L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus, S thermophilus as a powder sachet.

• Dose (probiotic): 9 x 10^11 (2 sachets).

• Frequency of administration: daily.

• Duration: 6 months.

Outcomes

Primary outcome measures

• Gastrointestinal symptoms measured using GIQLI, mean change from baseline.

• HRQoL measured using the short form 12 (SF‐12), mean change from baseline.

Time points for measurements: baseline, 6 months.

Length of follow‐up: 24 weeks.

Identification

Sponsorship source: no stated.

Country: Spain.

Setting: Cystic Fibrosis Unit, Hospital.

Author's name: Rosa del Campo.

Institution: Cystic Fibrosis Unit, Hospital Universitario Ramón y Cajal, Madrid, Spain.

Email: [email protected].

Address: Servicio de Microbiología, Hospital Universitario Ramón y Cajal. Ctra. Colmenar Km 9,1. 28034 Madrid, Spain.

Funding Source

Not specified.

Declaration of Interest Among the Primary Researchers

Not specified.

Notes

Abstract only.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomized protocol assigned correlatively"

Judgement comment: randomisation not specified.

Allocation concealment (selection bias)

Unclear risk

Judgement comment: no specified allocation concealment method.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "capsule/day of CasenBiotic, (CasenFleet), and group B consumed 2 package/day of VLS3 (Faes Farma)."

Judgement comment: no clear blinding process. Both groups consumed probiotics and one intervention was given in a capsule and the other as a powder in a sachet.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Judgement comment: no clear blinding process.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Judgement comment: unclear how many were enrolled and how many completed.

Selective reporting (reporting bias)

Unclear risk

Judgement comment: specific results not reported in the abstract. Adverse events not reported.

Other bias

Unclear risk

Judgement comment: unclear funding source or other sources of bias given abstract.

Methods

Trial design: RCT.

Trial grouping: cross‐over, without a washout period.

Randomisation method: not specified, performed by the Biostatistics Unit of Hospital Ramón y Cajal.

Participants

Incluson criteria

• Fully‐informed individuals with CF.

• Aged older than 4 years who consented (their parents if under 18 years old) to participate.

Excluded criteria

• Terminal stage of the disease.

• Acute pulmonary exacerbation.

• Immune‐deficient condition.

Baseline characteristics

Overall

• Participants: n = 30.

• Age, median (range) years: 17.7 (4 ‐ 44).

• Gender distribution, number (%) males: 21 (70%).

• Pancreatic insufficient, number (%): 11 (37%).

• BMI, median (range) kg/m²: 19.9 (17.6 ‐ 24.5).

• FEV₁ % predicted, median (range): 77.0% (32% ‐ 118%).

Interventions

Probiotic

• Preparation: L reuteri DSM 17938 (1 x 10⁸ CFU/day) chewable tablet.

• Dose (probiotic): 1 x 10⁸ CFU/day.

• Frequency of administration: daily.

• Duration: 6 months.

Placebo

• Preparation: chewable tablet (contents not specified).

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 6 months.

Outcomes

Primary outcome measures

• Gastrointestinal symptoms measured using GIQLI, post treatment absolute mean.

• HRQoL measured using the short form 12 (SF‐12), post treatment absolute mean.

• Weight (kg), post treatment absolute mean.

• Height (m), post treatment absolute mean.

• BMI (kg/m²), post treatment absolute mean.

• Lung function (FEV₁ % predicted and MMEF 25 ‐ 75%), post treatment absolute mean.

• Faecal fat absorption measured by NIRA (gr%), post treatment absolute mean.

• Fat absorption coefficient (%), post treatment absolute mean.

• Faecal calprotectin (µg/g), post treatment absolute mean.

• Faecal inflammatory interleukins: IL‐8, IL‐1β, IL‐6, IL‐10, TNF‐α and IL‐12p70 (pg/ml), post treatment absolute mean.

Secondary outcome measures

• Adverse events including serious adverse reactions, adverse reactions and mortality.

• Metagenomic analysis of faecal microbiota using tag‐encoded 16S rRNA gene pyro‐sequencing, post treatment relative abundance of bacterial phyla and sequence density.

Time points for measurements: 6 months.

Length of follow‐up: 24 weeks.

Identification

Country: Spain.

Setting: 2 separate CF‐Units in Spain (Madrid and Granada).

Author's name: Rosa del Campo.

Institution: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.

Email: [email protected].

Address: Servicio de Microbiología, Hospital Universitario Ramón y Cajal. Ctra. Colmenar Km 9,1. 28034 Madrid, Spain.

Funding Source

FP‐7‐HEALTHF3‐2011‐EVOTAR‐282004 project and the PI12/00734 and PI13/00205 projects supported by Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) and co‐financed by the European Development Regional Fund “A Way toAchieve Europe,” ERDF, and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).

BioGaia provided the placebo formulation.

Declaration of Interest Among the Primary Researchers

No declaration made.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomized".

Judgement comment: Randomisation not specified.

Author correspondence: The Biostatistics Unit of Hospital Ramón y Cajal prepared the randomisation.

Allocation concealment (selection bias)

Unclear risk

Judgement comment: allocation method not specified.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Only the manufacturers knew the significance of the product labels and the double blind code was opened only at the end of the study".

Quote: "Active and placebo tablets and packaging were identical".

Judgement comment: only manufacturer knew labels of probiotic and placebo so all participants and personnel should have been blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: unblinding only at the end of the trial.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "although finally only 25 pairs offered sufficient quality results, due to bad processing or abundance of unspecific sequences".

Quote: "Thirty‐nine CF patients were initially enrolled, and 30 completed the entire protocol".

Judgement comment: 23% of participants did not complete the entire protocol.16S rRNA analysis only included 25/30 pairs of samples (83%).

Selective reporting (reporting bias)

High risk

Quote: "Anthropometric data, clinical status, antibiotic treatments, hospital admittances".

Judgement comment: no protocol available, unclear if clinical status data (listed) were collected throughout as not presented.

Judgement comment: 3 Spanish hospitals reported in 2013 abstract (Oral presentation in the 36th ECFC, Lisbon, 2013), however only 2 centres reported in this article.

Other bias

Unclear risk

Judgement comment: cross‐over study design with no true baseline data collected. Post‐probiotic and post‐placebo data pooled. Competitive grant funding. No conflicts reported.

Methods

Trial design: RCT.

Trial grouping: cross‐over, without a washout period.

Randomisation method: not specified.

Participants

Inclusion criteria

• Children with CF.

Exclusion criteria

• Not specified.

Baseline characteristics

• Participants: n = 24.

• Age, median (range) years: 9 (5).

• Gender distribution, number (%) males: 13 (54.2%).

Interventions

Probiotic

• Preparation: L rhamnosus strain GG (6x 10⁹ CFU/day) dissolved in ORS.

• Dose (probiotic): 6x 10⁹ CFU/day

• Frequency of administration: daily.

• Duration: 6 months.

Placebo

• Preparation: ORS.

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 6 months.

Outcomes

Primary outcome measures

• Weight (kg), mean change from baseline.

• Incidence of abdominal pain (defined as pain on a daily basis for at least 3 days recurring at least 3 times per month for at least 3 months).

• Number of episodes of infections requiring antibiotic treatment.

• Steatorrhoea (measured using steatocrit method).

• Serum iron levels, mean change from baseline.

Time points for measurements: onset, end of treatment administration, and end of subsequent placebo administration.

Length of follow‐up: 52 weeks.

Identification

Country: Italy.

Setting: CF Centre.

Author's name: Alfredo Guarino.

Institution: Department of Pediatrics, University of Naples ‘‘Federico II’’, Via S. Pansini 5, 80131 Naples, Italy.

Email: [email protected].

Funding Source

Not specified.

Declaration of Interest Among the Primary Researchers

No declaration.

Notes

Abstract only.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "randomly assigned".

Judgement comment: not sure method of randomisation.

Allocation concealment (selection bias)

Unclear risk

Judgement comment: not specified.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "child's family was blind to the treatment or placebo regimen".

Judgement comment: participants blinded to treatment however investigators not.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Judgement comment: outcome assessors not clearly blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Judgement comment: all 24 children included.

Selective reporting (reporting bias)

Low risk

Judgement comment: all outcome measures reported in abstract. Adverse events not reported.

Other bias

Low risk

Judgement comment: no conflicts reported in abstract.

Methods

Trial design: RCT.

Trial grouping: parallel group.

Randomisation method: random permuted blocks algorithm.

Participants

Inclusion criteria

• People with CF diagnosed based on elevated sweat chloride concentration (> 60 mEq/L).

• FEV₁ over 70% predicted.

• No inhaled or systemic steroids.

• No antiinflammatory drugs, anti‐leukotrienes, and mast cell membrane stabilizers.

• No serious organ involvement.

Exclusion criteria

• History of pulmonary exacerbation or upper respiratory infection in the previous 2 months.

• Change of medication in the last 2 months.

• History of haemoptysis in the last 2 months.

• Colonization with Burkholderia cepacia or mycobacteria.

Pretreatment: mean (SD) values for FEV1 % predicted for probiotic and placebo groups were 94.7% (15.4) and 97.5% (15.2) respectively (not significant).

Baseline characteristics

Overall

• Participants: n = 61.

• Age, mean (SD) years: 17.5 (6 ‐ 29).

• Gender distribution, number (%) males: 39 (64%).

• F508del / F508del, number (%): 33 (54%).

Probiotic

• Participants: n = 30.

• Age, mean (SD) years: 19.1 (7.3).

• Gender distribution, number (%) males: 19 (63%).

• F508del / F508del, number (%): 15 (50%).

• FEV₁ % predicted, mean (SD): 94.7% (15.4%).

• Age of P aeruginosa colonisation, mean (range) years: 7.5 (2 ‐ 14).

Placebo

• Participants: n = 31.

• Age, mean (SD) years: 17.2 (6.3).

• Gender distribution, number (%) males: 20 (65%).

• F508del / F508del, number (%): 18 (58%).

• FEV₁ % predicted, mean (SD): 97.5% (15.2%).

• Age of P aeruginosa colonisation, mean (range) years: 8.1 (1 ‐ 16).

Interventions

Probiotic

• Preparation: L reuteri ATCC55730 (10¹⁰ CFU/day)

• Dose (probiotic): 5 drops (10¹⁰ CFU/day).

• Frequency of administration: daily.

• Duration: 6 months.

Placebo

• Preparation: placebo drops (contents not specified).

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 6 months.

Outcomes

Primary outcome measures

• Number of pulmonary exacerbations (defined using CF Foundation Criteria).

• Duration (days) of antibiotic therapy for pulmonary exacerbations.

• Number and duration (days) of hospitalisation for pulmonary exacerbations.

• Number of gastrointestinal tract infections (diarrhoea with 3 loose or watery stools within 24 hours with or without vomiting), confirmed by physicians of the CF staff.

• Number of respiratory tract infections (rhinitis, pharyngitis, sinusitis and otitis), confirmed by physicians of the CF staff.

Secondary outcome measures

• Adverse events including serious adverse reactions, adverse reactions and mortality.

• Lung function (FEV₁ % predicted), mean change from baseline.

• Faecal calprotectin (µg/g), mean change from baseline.

• Change in qualitative and quantitative bacteria present in sputum.

• Sputum inflammatory interleukins: IL‐8 and TNF‐α (pg/ml), mean change from baseline.

• Serum inflammatory interleukins: IL‐8 and TNF‐α (pg/ml), mean change from baseline.

Time‐points for measurements: baseline, 6 months.

Length of follow‐up: 26 weeks.

Identification

Country: Italy.

Setting: Regional Center for CF of the Department of Pediatrics, University of Rome "La Sapienza".

Author's name: Laura Stronati.

Institution: ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Rome, Italy.

Email: [email protected].

Address: Section of Toxicology and Biomedical Sciences, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, ENEA – Via Anguillarese 301, 00123 Rome, Italy.

Funding Source

Italchimici (Pomezia, Italy) supplied probiotic and placebo.

Declaration of Interest Among the Primary Researchers

The authors report no conflicts of interest.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "allocation schedule was computer generated, using a random permuted blocks algorithm".

Judgement comment: appropriate sequence generation.

Allocation concealment (selection bias)

Low risk

Quote: "The allocation schedule was fully concealed from the doctors working in the Regional Center for CF who recruited patients to the study".

Judgement comment: appropriate allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The unblinding procedures were performed after the study was completed and the statistical analysis carried out".

Quote: "The placebo was packed in identical bottles, had the same colour, weight, smell, and taste of the probiotic formulation".

Judgement comment: participants and personnel adequately blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Outcome measures of efficacy were recorded by investigators totally unaware of LR or placebo administration to patients".

Judgement comment: adequate blinding of assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "A premature discontinuation occurred only in 1 of the placebo group for with‐ drawn consent after randomisation".

Judgement comment: 61 randomised, 1 (1.6%) withdrew consent after randomisation (placebo).

Selective reporting (reporting bias)

Unclear risk

Quote: "The duration in days of each episode corresponded to the duration of the antibiotic therapy".

Judgement comment: number of days for treatment of pulmonary exacerbation not presented.

Other bias

Low risk

Quote: "Both products were supplied by Italchimici (Pomezia, Italy), who had no role in the conception, design, conduct of the study, or in the analysis and interpretation of the data".

Judgement comment: the authors report not conflicts and pharmaceutical company played no role in study.

Methods

Trial design: RCT.

Trial grouping: parallel group.

Randomisation method: simple randomisation.

Participants

Inclusion criteria

• Participants with CF, diagnosed with 2 positive sweat tests.

• Children aged between 4 and 18 years.

• Pancreatic insufficiency.

Exclusion criteria

• Non‐steroidal anti‐inflammatory drug (NSAID) during the last 2 weeks.

• On antibiotic therapy at the time of the study.

Baseline characteristics

Overall

• Participants: n = 47.

• Pancreatic insufficient, number (%): 47 (100%).

Probiotic

• Participants: n = 24.

• Age, mean (SD) years: 8.56 (4.19).

• Pancreatic insufficient, number (%): 24 (100%).

Placebo

• Participants: n = 23.

• Age, mean (SD) years: 8.65 (3.29).

• Pancreatic insufficient, number (%): 23 (100%).

Interventions

Probiotic

• Preparation: Protexin Restor sachet, which contains of FOS and a mixture of 1x 10⁹ CFU/sachet bacteria (L casei, L rhamnosus, S thermophilus, B breve, L acidophilus, B infantis, L bulgaricus).

• Dose (probiotic): 1g sachet (1x 10⁹ CFU/sachet).

• Frequency of administration: daily.

• Duration: 1 month.

Placebo

• Preparation: 1g maltodextrin (sachet)

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 1 month.

Outcomes

Primary outcome measures

• Faecal calprotectin (µg/g), mean change from baseline

Time points for measurements: baseline, 1 month.

Length of follow‐up: 4 weeks.

Identification

Country: Iran.

Setting: The Pediatrics Center of Excellence in Iran.

Author's name: Nima Rezaei.

Institution: Molecular Immunology Research Center, and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran.

Email: [email protected].

Address: Children Medical Center, 62 Gharib St, 14194 Tehran, Iran.

Funding Source

Sponsored by Tehran University of Medical Sciences.

Declaration of Interest Among the Primary Researchers

No conflicts disclosed.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were simply randomly divided into two groups".

Judgement comment: unclear about method of randomisation.

Allocation concealment (selection bias)

Unclear risk

Judgement comment: not specified.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "As a double‐blind study, neither the patients nor the doctors/researchers were aware of the placebo or probiotic packs".

Judgement comment: participants and personnel all blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: not specified but outcome measure objective.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Although 50 patients were initially selected for this study, three patients later decided not to participate in this study and did not bring the stool samples. Therefore, 47 patients were enrolled in the study".

Judgement comment: 50 participants enrolled and 47 randomised (all included).

Selective reporting (reporting bias)

Low risk

Judgement comment: stool calprotectin only outcome measure reported. Consistent with the protocol. Adverse events not reported.

Other bias

Low risk

Judgement comment: sponsored by Tehran University of Medical Sciences. No conflicts disclosed.

Methods

Trial design: RCT.

Trial grouping: parallel group.

Randomisation method: not specified, "randomly divided".

Participants

Inclusion criteria

• CF with a positive elevated sweat chloride concentration (> 60 mEq/L), clinical symptoms and common mutations.

• Aged 2 ‐ 12 years.

• Absence of chronic illnesses other than CF.

• Informed consent by parents.

Exclusion criteria

• Congenital heart disease.

• Abnormalities of the central nervous system.

• Intolerance to the medication.

• No parental consent.

• Inability to consume probiotic because of severe disease.

Baseline characteristics

Overall

• Participants: n = 37.

• Gender distribution, number (%) males: 20 (54.1%).

• Pancreatic insufficient (number; %): 37 (100%).

Probiotic

• Participants: n = 20.

• Age, median (range) years: 5.36 (2.66).

• Gender distribution, number (%) males: 13 (65%).

• Pancreatic insufficient (number; %): 20 (100%).

Placebo

• Participants: n = 17.

• Age, median (range) years: 5.50 (2.55).

• Gender distribution, number (%) males: 7 (41.2%).

• Pancreatic insufficient (number; %): 17 (100%).

Interventions

Probiotic

• Preparation: Protexin capsule containing L casei, L rhamnosus, S thermophilus, B breve, L acidophilus, B infantis, and L bulgaricus.

• Dose (probiotic): 2 x 10⁹ CFU/day (2 capsules).

• Frequency of administration: daily.

• Duration: 1 month.

Placebo

• Preparation: capsule (contents not specified).

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 1 month.

Outcomes

Primary outcome measures

• HRQoL measured using the PedsQL^TM 4.0 SF 15, post treatment absolute mean 3 and 6 months after completing the intervention period.

• Number of pulmonary exacerbations (defined using CF Foundation Criteria), post treatment absolute mean 3 months after completing the intervention period.

• Duration (days) of hospitalisation for pulmonary exacerbations.

Time points for measurements: baseline, 1 month (end intervention), 4 months (3 months post treatment) and 7 months (6 months post treatment).

Length of follow‐up: 30 weeks.

Identification

Country: Iran.

Setting: Dr. Sheikh Pediatric Hospital CF clinic, Mashhad, Iran.

Author's name: Atieh Mehdizadeh‐Hakkak.

Institution: Cystic Fibrosis Clinic, Dr. Sheikh Pediatric Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

Email: [email protected].

Address: Number 21, 12th Felestin Street, Mashhad, Iran.

Funding Source

Research Chancellor of Mashhad University of Medical Sciences.

Declaration of Interest Among the Primary Researchers

No conflicts of interest.

Notes

The authors have compared probiotic participants with themselves in the previous year instead of against the placebo cohort; these data were not included in our review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomly divided into two groups of probiotic and placebo".

Judgement comment: randomisation process not specified.

Allocation concealment (selection bias)

Unclear risk

Judgement comment: not specified.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "placebo capsules which contained all ingredients of probiotic capsules except the effective substance".

Judgement comment: participants were blinded. Protocol states investigators were not blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The questionnaires were filled out by a trained nurse who was unaware about the principles of study".

Judgement comment: HRQoL assessment blinded. Pulmonary exacerbation assessment not blinded but defined based on consensus criteria.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All patients enrolled in both groups (placebo group: 7 females, 13 males, mean age 5.36±2.66 years; placebo group: 10 females, 7 males, mean age 5.50±2.55 years) completed the study period".

Judgement comment: all participants completed.

Selective reporting (reporting bias)

High risk

Judgement comment: growth outcomes (weight, height, head circumference and arm circumference) included in protocol (IRCT201205219823N1 ‐ this differs from registration number listed in the article which cannot be found) and not reported in paper. Also unclear why pulmonary exacerbations were not compared between probiotic and placebo groups. Adverse events not reported.

Other bias

Unclear risk

Judgement comment: unclear if Probiotics International Company, UK also provided the placebo product and if they had any influence on the study.

Methods

Trial design: RCT.

Trial grouping: cross‐over design.

Randomisation method: not specified.

Participants

Inclusion criteria

• Mild to moderate CF.

• At least 3 pulmonary exacerbations requiring antibiotics per year.

• P aeruginosa in the sputum.

• Able to produce sputum.

Exclusion criteria

• Severe pulmonary disease.

• Less than 3 pulmonary exacerbations per year.

• Unable to produce sputum.

Baseline characteristics

Overall

• Participants: n = 12 (terminated early).

Interventions

Probiotic

• Preparation: 2.5×10¹⁰ CFU/day; L acidophilus, B bifidum, L rhamnosus, L lactis, L casei, B breve, S thermophilus, B longum, L paracasei, L plantarum, B infantis (Bio‐25 probiotic).

• Dose (probiotic): 2.5×10¹⁰ CFU/day (2 tablets).

• Frequency of administration: daily.

• Duration: 6 months.

Placebo

• Preparation: tablet (contents not specified).

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 6 months.

Outcomes

Primary outcome measure

• Rate of pulmonary exacerbations (requiring IV and oral antibiotic treatment).

Secondary outcome measures

• Sputum bacteria.

• Sputum inflammatory markers.

• Gastrointestinal inflammation.

Time points for measurements: not specified.

Length of follow‐up: not specified.

Identification

Country: Israel.

Setting: Edmond and Lily Safra Children's Hospital, Sheba Medical Center.

Author's name: Dr Batia Weiss.

Institution: Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Israel.

Email: [email protected].

Address: Emek Ha’ela 31, Ramat Gan, Israel.

Funding Source

Not specified.

Declaration of Interest Among the Primary Researchers

Not specified.

Notes

Trial was terminated in December 2013 after a severe allergic reaction (severe urticaria) for 1 participant in the probiotic group. 12 participants were enrolled at the time of termination.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information available.

Allocation concealment (selection bias)

Unclear risk

Insufficient information available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information available.

Selective reporting (reporting bias)

Unclear risk

Insufficient information available.

Other bias

Unclear risk

Blinding of outcome assessment (detection bias).

Methods

Trial design: RCT.

Trial grouping: cross‐over, with a 1‐month washout period.

Randomisation method: not specified.

Participants

Inclusion criteria

• CF diagnosis: 2 sweat tests with chloride > 60 meq/L.

• Clinically stable: no need for acute antibiotic treatment at start of trial.

• Pre‐pubertal children.

• Able to perform pulmonary function test.

• Preventive antibiotic treatment or antibiotic inhalation is allowed as long as taken 2 hours apart from probiotic and continued throughout the trial.

• Assent from the child and consent from parents or guardian.

Exclusion criteria

• Recent CF diagnosis (less than 6 months).

• Commenced tube feeding in 6 months prior to trial.

• Oral or intravenous antibiotic treatment in the last month.

• Oral or IV steroid treatment in the last 2 months.

• New CF complications in the last 3 months: diabetes, liver disease.

• New colonisation in the past 3 months.

Baseline characteristics

Overall

• Participants: n = 31.

• Age, median (range) years: 9.3 (6.9 ‐ 12.2).

• Gender distribution, number (%) males: 13 (41.9%).

• F508del / F508del, number (%): 12 (38.7%).

• Pancreatic insufficient, number (%): 26 (83.9%).

• BMI, median (range) z score: ‐0.5 (‐1.5 ‐ 0.08).

• FEV₁ % predicted, median (range): 100% (87.2% ‐ 106.6%).

Interventions

Probiotic

• Preparation: L rhamnosus SP1 (DSM 21690) and B animalis lactis spp. BLC1 (LMG 23512)® Vésale Pharma (vial, preparation not specified).

• Dose (probiotic): 10¹⁰ CFU/day.

• Frequency of administration: daily.

• Duration: 4 months.

Placebo

• Preparation: placebo (vial, preparation not specified).

• Dose (probiotic): 0.

• Frequency of administration: daily.

• Duration: 4 months.

Outcomes

Primary outcome measures

• Number of pulmonary exacerbations (defined as a period where, due to increased pulmonary symptoms, a patient was treated with antibiotics).

• Duration (days) of antibiotic therapy for pulmonary exacerbations.

• BMI (z score), post treatment absolute mean.

• Height (z score), post treatment absolute mean.

• Weight (z score), post treatment absolute mean.

• Lung function (FEV₁ % predicted), post treatment absolute mean.

• Lung function (FVC % predicted), post treatment absolute mean.

• Days of abdominal pain.

• Faecal calprotectin (mg/kg), post treatment absolute mean.

• Gut permeability test using lactulose/mannitol, measuring urinary lactulose/mannitol; normal intestinal permeability (defined as < 0.03), % normal.

Secondary outcome measures

• Adverse events including serious adverse reactions, adverse reactions and mortality.

• Serum CRP (mg/mL).

• Serum total IgG (pg/mL).

Time points for measurements: baseline, 4 months (end), 5 months (washout) and 9 months (end).

Length of follow‐up: 39 weeks.

Identification

Sponsorship source: not stated.

Country: Belgium.

Setting: 3 CF centres (Ghent, Antwerp and Brussels).

Authors name: S. Van Biervliet.

Institution: Ghent University Hospital.

Email: [email protected].

Address: Ghent University Hospital, Ghent, Belgium.

Funding Source

A company (Vésale Pharma) provided the probiotic. No funding source(s) declared.

Declaration of Interest Among the Primary Researchers

No conflicts of interest statement declared.

Notes

In the first phase, 17 and 14 participants commenced the probiotic and placebo respectively.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Judgement comment: not specified; randomisation provided by the company who provided the probiotic.

Allocation concealment (selection bias)

Unclear risk

Judgement comment: not specified.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "A double blind cross over study".

Judgement comment: probiotic and placebo vials were differentiated only by a number (personal communication).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Judgement comment: outcome assessors were blinded (personal communication).

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "we didn't reach the acquired number needed to treat to draw firm conclusions".

Quote: "31 patients agreed, only 25 finished (3 non‐starters, 1 stopped due to diarrhoea, 2 not compliant)".

Judgement comment: 20% of participants did not finish.

Selective reporting (reporting bias)

High risk

Quote: "a blood sample was taken for analysis of CRP and total IgG".

Judgement comment: most reported outcomes presented but serum CRP and IgG not presented. No published protocol available.

Other bias

Low risk

Judgement comment: no conflicts identified.