Supplementary Material

Brazilian guidelines for the pharmacological treatment of the pulmonary symptoms of cystic fibrosis. Official document of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association)

Diretrizes brasileiras para o tratamento farmacológico pulmonar na fibrose cística. Documento oficial da Sociedade Brasileira de Pneumologia e Tisiologia)

 
References cited in this supplemental material follow the numbering of the list of references cited in the main article. References cited only in this supplemental material are cited here with numbering subsequent to the list of references in the main text.
 
Question S1. Detailed description of the findings.
 
For this question, the outcomes categorized as critical by the committee were mortality, adverse effects, and quality of life. Outcomes such as pulmonary function (FEV1), BMI variation, and exacerbations were also evaluated and were categorized as important.
 
Regarding mortality, the effect of the treatment could not be estimated, because there were no deaths in any of the randomized clinical trials (RCTs) evaluated(12,32,35-37,39,47,48) or in the placebo groups of any of the observational studies evaluated.(28-31,34,38,40-46,49-54)
 
All of the studies used the Cystic Fibrosis Questionnaire-Revised (CFQ-R) in the respiratory symptoms domain(167) to assess quality of life. Pooled effect measures showed better quality for patients who were being treated with ivacaftor, in the RCTs (relative risk [RR] =6.46; 95% CI: 2.29-10.64) and in the observational studies (RR = 10.23; 95% CI: 5.08-15.38).
 
There was a higher occurrence of adverse events with the use of ivacaftor, with an RR of 1.46 (95% CI: 1.21-1.77) in the RCTs. However, serious adverse events that led to treatment discontinuation were rare, which supports the good safety profile of the drug.
 
For the outcomes categorized as important, the analysis of the studies allowed us to infer an improvement in pulmonary function (FEV1) with the use of ivacaftor on the order of 8.52% (95% CI: 4.05-13.00) in the RCTs and 6.71% (95% CI: 5.49-7.93) in the observational studies. The treatment was associated with a reduction in the rate of exacerbations, with an RR of 0.66 (95% CI: 0.48-0.91) in the RCTs and 0.67 (95% CI: 0.63-0.70) in the observational studies.
 
In a real-life study published in 2020, Volkova et al.(55) evaluated disease progression in patients treated with ivacaftor for 5 years. The authors evaluated patients enrolled in cystic fibrosis (CF) registries in the US and UK, which maintain a high degree of data integrity. They analyzed 635 cases versus 1,875 controls in the US registry and 247 cases versus 1,230 controls in the UK registry. The authors also observed that, at the end of the 5-year follow-up period, the ivacaftor group patients had better lung function and a better nutritional status, as well as a lower frequency of exacerbations and hospitalizations, in comparison with their baseline values and the values obtained for the standard therapy without ivacaftor (control) group. Although the UK registry included fewer patients, the outcomes were similar. In addition, there were trends toward improvement in other relevant outcomes, such as a lower frequency of CF-related diabetes and a lower prevalence of chronic infection with Pseudomonas aeruginosa. Such findings in a real-life study(55) indicate that the modulator ivacaftor is indicated for the treatment of CF patients who carry the eligible genetic variants.
 
Question S2. Detailed description of the findings.
 
The outcomes categorized as critical by the committee were mortality, adverse effects, and quality of life. Outcomes such as pulmonary function (FEV1), BMI variation, and exacerbations were also evaluated and considered important.
 
As for mortality, it was not possible to estimate the effect of treatment. In the 2 RCTs (12.57) there were no deaths in the intervention groups (a total of 840 patients). In the evaluation of the observational studies (1,407 subjects included), only 6 deaths occurred.
 
All studies used the CFQ-R in the respiratory symptoms domain to assess quality of life.(12,56-69) By using the data from the studies, it was possible to perform a meta-analysis. The pooled effect measure for the RCTs (RR = 2.5; 95% CI: 0.1-5.1) was similar to that obtained for the observational studies (RR = 3.82; 95% CI: 2.28-5.36), showing that the score for the CFQ-R respiratory symptoms domain was higher among the patients who were being treated with lumacaftor+ivacaftor. Despite the numerical improvement observed in quality of life, the result did not reach the necessary clinical significance of 4 points established in the score.
 
In all of the studies included, the proportion of patients reporting adverse events was described. The frequency of adverse events ranged from 59.4% to 96.5% in the treatment groups. The most commonly reported events were respiratory manifestations of mild to moderate severity, including dyspnea, chest tightness or discomfort, and bronchospasm. It is noteworthy that comparisons using appropriate statistical tests were not presented. The studies converged to a good safety profile regarding the use of lumacaftor+ivacaftor, although the quality of evidence was very low.
 
Two RCTs (12.57) evaluated the annual exacerbation rate and found it to be lower in the treatment group (RR = 0.65; 95% CI: 0.55-0.75), although the quality of evidence was very low. It was not possible to estimate the effect on exacerbation prevention in observational studies because of the lack of control groups. With regard to BMI, the use of lumacaftor+ivacaftor was found to provide a slight improvement in this index, in the RCTs (gain of 0.26 kg/m2; 95% CI: 0.17-0.35) and in the observational studies (gain of 0.36 kg/m2; 95% CI: 0.03-0.69).
 
The pooled effect measure for lung function showed an increase in FEV1 of 2.98% (95% CI: 2.31-3.64) in the 2 RCTs,(12,57) and the results found were considered consistent. In the observational studies evaluated, the increase found was 2.17% (95% CI: 0.92-3.41), although the quality of evidence was very low.
 
Question S3. Detailed description of the findings.
 
For this question, the outcomes categorized as critical by the committee were mortality, adverse effects, and quality of life. Outcomes such as pulmonary function (FEV1), BMI variation, and exacerbations were also evaluated and were categorized as important.
 
There were 4 RCTs that reported data on mortality. (14,15,74,75) None of those studies, involving a collective total of 452 patients in the control groups and 573 patients in the tezacaftor+ivacaftor groups, identified fatal events.
 
Four studies assessed quality of life using the CFQ-R.(13,14,70,72) One observational study(72) showed an increase of 3.4 points (95% CI: 1.4-5.5). The meta-analysis carried out with results from 3 other studies(13,14,70) showed an increase of 6.02 points (95% CI: 1.40-10.64), although the quality of evidence was very low.
 
Adverse effects were assessed and compiled. There was no statistically significant difference between the groups treated with tezacaftor+ivacaftor and the control groups, with a rate ratio of 1.07 (95% CI: 0.93-1.22).
 
Lung function was assessed using FEV1, and the pooled effect measure showed an increase of 3.84% (95% CI: 2.23-5.45). The results found were considered consistent.
 
Two studies evaluated the annual exacerbation rate and found a lower rate in the intervention group.(13,14) However, the pooled analysis of the data did not show a statistically significant difference (RR = 0.68; 95% CI: 0.47-1.01). Regarding BMI, there is little evidence regarding the effect of tezacaftor+ivacaftor, and no differences were identified in relation to the control group in the studies evaluated.(13,70,72)
 
Question S4. Detailed description of the findings.
 
For this question, the critical outcomes analyzed were mortality, adverse events, and time free from infection with P. aeruginosa. The outcomes of microorganism eradication and pulmonary function, both categorized as important, were also analyzed. For the important outcomes of BMI and exacerbations, no studies were identified that would allow the effect that the treatment has on those outcomes to be evaluated.
 
Regarding the critical outcome of mortality, it was possible to select for analysis only one observational study,(86) in which the patients were followed for 56 days. In that study, there were no deaths in either group: that of patients receiving tobramycin for 28 days; and that of patients receiving tobramycin for 56 days. The quality of evidence was considered very low.
 
For the critical outcome of adverse events, an RR of 1.76 (95% CI: 1.14-2.74) was obtained for the eradication treatment, compared with placebo, in only 1 of the RCTs analyzed,(89) with very low quality of evidence.
 
One observational study(86) was selected to evaluate the critical outcome of time free from infection with P. aeruginosa with the eradication treatment, over a follow-up period of 6 months. The authors found that the time free from such infection was 23.75 months (95% CI: 12.50-34.40). It is noteworthy that the quality of evidence was very low.
 
With regard to the important outcome of eradication of P. aeruginosa, we analyzed only one RCT,(91) which demonstrated an RR of 1.43 (95% CI: 0.88-2.36), favoring treatment over placebo, with very low quality of evidence.
 
In the evaluation of the important outcome of lung function, 10 studies were selected, of which 7 were observational studies(76-80,82,87) and 3 were RCTs.(81,84,89) However, because of the heterogeneity of the measures used in the studies and the lack of comparison with placebo groups in the RCTs, only 4 observational studies were submitted to meta-analysis. A mean increase in FEV1 of 5.81% of the predicted value (range, 2.02-9.60) was obtained in the treated group, with very low quality of evidence.(81-83)
 
Question S5. Detailed description of the findings.
 
For this question, the outcomes categorized as critical by the committee were mortality, adverse effects, and quality of life. Outcomes such as pulmonary function (FEV1), BMI variation, and exacerbations were also evaluated and were categorized as important.
 
 Regarding the outcome of mortality, the result of the analysis of 6 RCTs showed a benefit in the treatment group compared with the placebo group (0.1% vs. 1.1%), with a protective effect (RR = 0.11; 95% CI: 0.01-0.85). (94,96,104,116,112,115)
 
Fifteen studies included in this review assessed the critical outcome of adverse events. Despite a large number of individuals studied, there was heterogeneity and inconsistency in several aspects, which made the analysis difficult. The adverse events most commonly reported were coughing, wheezing, hemoptysis, and throat irritation. There were 977 events among 777 patients (a rate of 125.7%) in the intervention group and 737 events among 575 patients (a rate of 128.2%) in the placebo group, with no statistical difference (RR = 0.98; 95% CI: 0.89-1.09).(95-97,99,101,102,104-106,111-114,116)
 
Three studies, all classified as RCTs, evaluated the quality of life of patients.(97,106,113) Two of those studies(97,106) assessed the scores on the respiratory symptoms domain of the CFQ-R, and only 1(113) assessed the total CFQ-R scores. All three studies showed that quality of life was more improved in the treatment group (mean increase of 6.4 points; range, 3.2-9.6) than in the placebo group.
 
Regarding the risk of exacerbations, the articles that evaluated the treatment with inhaled antimicrobials for chronic infection with P. aeruginosa obtained conflicting results, making it impossible to clearly state whether there was a benefit from the treatment in terms of a reduction in the number of pulmonary exacerbations. The analysis showed no statistically significant difference.(100,101,103,110,117)
 
For the assessment of lung function, some studies have shown improvement in FEV1 and FVC in the group treated with inhaled tobramycin or colistimethate when compared with controls.(111,112,117) In the present review, we identified a benefit of the treatment, with mean values that were 2.24% higher (95% CI: 0.17-4.30) in the RCTs(94-100,104-108,110-116,118) and 2.25% higher (95% CI: 2.89-7,39) in the observational studies. (101-103,109,117) It should be noted, however, that there was great heterogeneity and inconsistency of findings among the studies.
 
Only 1 study,(111) with an observational design, evaluated the impact that treatment for chronic infection had on BMI, and that study showed no significant differences.
 
Question S6. Detailed description of the findings.
 
For this question, the outcomes categorized as critical by the committee were mortality, adverse effects, and quality of life. Outcomes such as pulmonary function (FEV1), BMI variation, and exacerbations were also evaluated and were categorized as important.
 
All of the studies evaluated the rate of success in eradicating methicillin-resistant Staphylococcus aureus.(120-127) In the two RCTs evaluated,(123,126) with follow-up periods of 28 days and 6 months, respectively, methicillin-resistant S. aureus was eradicated successfully (OR = 3.12; 95% CI: 1.7-5.7). It was not possible to evaluate two other critical outcomes: mortality and adverse events. As for the quality of life outcome, the results were not significant.
 
Three studies evaluated exacerbations(121,123,124) but did not report consistent results regarding differences with the control groups. Only 1 study did not assess lung function.(121) In the 2 RCTs that evaluated the gain in FEV1,(123,126) an absolute gain of 5.8% of the predicted value (95% CI: 1.02-10.62) was observed.
 
Question S7. Detailed description of the findings.
 
For this question, the outcomes categorized as critical by the committee were mortality, adverse effects, and quality of life. Outcomes such as pulmonary function (FEV1), BMI variation, and exacerbations were also evaluated and were categorized as important.
 
For the outcomes of mortality(17,149) and adverse effects,(17,143,146,149) no significant differences were observed with the use of dornase alfa. When assessing quality of life, an observational study of 152 patients reported a mean increase in the CFQ-R score of 7.38 points (95% CI: 4.24-10.52), although that study did not evaluate a control group (very low quality of evidence). In the only RCT analyzed,(155) no significant difference in quality of life was demonstrated with the use of dornase alfa.
 
Treatment with dornase alfa resulted in an improvement in FEV1 (% of the predicted value) in 9 RCTs, which collectively analyzed 2,509 patients and showed a mean improvement in FEV1 of 5% (95% CI: 1.65-8.35) (17,131-134,141,152-154) and in 12 observational studies,(136-139,143,146-148,150,156,157,161) which collectively analyzed 5,303 patients and showed a mean improvement in FEV1 of 4.89% (95% CI: 1.42-8.35), although the quality of evidence was very low. A significant reduction in exacerbations (RR = 0.73; 95% CI: 0.54-0.91) was also identified in 2 RCTs,(17,152) with high quality of evidence. No significant differences were observed regarding BMI.
 
Question S8. Detailed description of the findings.
 
For this question, the outcomes categorized as critical by the committee were mortality, the eradication rate, adverse effects, and quality of life. Outcomes such as pulmonary function (FEV1), BMI variation, and exacerbations were also evaluated and were categorized as important.
 
It was not possible to estimate the effect that eradication therapy had on mortality or on the eradication rate.
 
In the clinical trial by Tullis et al.(165) the number of adverse events, especially bronchospasm, was found to higher in the group treated with inhaled aztreonam than in the placebo group.
 
Eradication therapy for Burkholderia cepacia complex was not found to have any effect on the outcomes categorized as important (exacerbations, BMI, lung function, and quality of life).
 
REFERENCES
 
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