In the present double-blind randomized placebo-controlled clinical trial, the CF patients were selected from Tabriz Children’s Hospital affiliated with Tabriz University of medical sciences. The diagnosis of CF was confirmed by a pediatrician according to clinical signs and two sweat chloride test (> 60 mmol/L). The children were included if they aged 5-12 years with Tiffeneau-Pinelli index>40% and the absence of recent acute exacerbation. The exclusion criteria were: having other related diseases such as liver or endocrine diseases, having ventilator-dependent respiratory failure, or had regular use of probiotics and probiotic fortified food were excluded from the study. Forty children with CF met inclusion/exclusion criteria and entered the study.
Written informed consent was obtained from all children's parents. This study was approved by The Ethics Committee of Tabriz University of Medical Sciences) IR.TBZMED.REC.1395.919). The protocol was registered at Iranian registry clinical trials (IRCT2017011732004N1).
Forty patients were randomly divided into intervention and placebo groups according to their age and sex. The detailed methods of randomization, blinding and deciding about patients’ adherence to study protocol were described in our previous publication . The sample size was calculated using the PASS 15.0 software and based on the result of the previous study  (changes in PedsQL total score in the synbiotic group: 2.37±1.17, and placebo group: 1.4±0.68) and considering the changes in PedsQL total score, 90% power, two-sided 5% significance and 20% drop-out rate. This necessitates the sample size of 20 participants in each group.
The patients in the intervention and placebo groups were instructed to consume two synbiotic or maltodextrin capsules per day for six months. The synbiotic supplement was purchased from Zist Takhmir company and it contains Lactobacillus casei (3.5 × 109 CFU/g), Lactobacillus acidophilus (1 × 109 CFU/g), Lactobacillus rhamnosus (7.5 × 108 CFU/g), Lactobacillus bulgaricus (108 × CFU/g), Streptococcus thermophilus (1 × 108 CFU/g), Bifidobacterium breve (1 × 1010 CFU/g), Bifidobacterium longum (3.5× 109 CFU/g) and 38.5 mg Fructo-oligosaccharides as prebiotic . The patients were asked to take capsules at least four-hours apart from antibiotics.
In this clinical trial, different outcomes including anthropometric measurements, hospitalization duration, antibiotic use, clinical outcomes, and quality of life were studied. All outcomes except the quality of life outcomes were reported in our previous study . In the present study, we reported the effect of synbiotic supplementation on HRQOL in children with CF.
The health-related quality of life was assessed using the Persian version of quality of life inventory questionnaires (PedsQL). The validity of the Iranian version of this questionnaire was investigated previously . The questionnaires had 23 items on a five-point Likert scale ranging from 0 (never a problem) to 4 (almost always a problem). According to the questionnaire instruction , the scores were transformed on a scale from 0 (score 4) to 100 (score 0) and the total score and dimensions scores were calculated by summing of the items over the number of items answered. The questionnaire includes the following dimension scores: physical (8 questions), emotional (5 questions), social (5 questions), and school functioning (5 questions). The final HRQoL total score and dimension scores were computed out of 100. A change of 4.4 in the PedsQL summary score was considered as the minimal clinically important difference (MCID) . The questionnaire was completed before and six months after supplementation
All analyses were conducted using SPSS 22.0 and based on intention to treat (ITT) analysis. The Kolmogorov-Smirnov test was used for checking the normality. The within-group comparisons were performed by paired sample t-test. The between-group analysis was done using independent sample t-test and chi-square tests. One way ANCOVA was used to compare the quality of life score after intervention by adjusting to the baseline values. The significance level was considered P-value ≤ 0.05.