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. 2023 Jun 14;2023(6):CD001506. doi: 10.1002/14651858.CD001506.pub5

Rosenfeld 2012.

Study characteristics
Methods RCT.
Design: double‐blind, parallel.
Duration: 48 weeks.
Location: 30 centres in USA and Canada.
Participants Total participants: n = 321 (176 males, 145 females) aged 4 ‐ 60 months with an established diagnosis of CF (details of diagnosis given in supplementary paper).
Age, mean (SD): HS group 2.2 (1.4) years; control group 2.3 (1.5) years.
Sex: HS group 84 males (53%); control group 92 males (56%).
Weight, mean (SD); HS group 12.2 (4.1) kg; control group 12.5 (4.1) kg.
Weight percentile, mean (SD): HS group 39.7 (28.1); control group 43.0 (29.1).
Height, mean (SD): HS group 84.8 (14.8) cm; control group 85.7 (15.0) cm.
Height percentile, mean (SD): HS group 36.9 (27.0); control group 39.9 (28.1).
Positive respiratory culture (Pseudomonas aeruginosa isolated from respiratory culture at or at any time prior to randomisation. For other organisms, positive culture at or within 24 months prior to randomisation):

  1. Pseudomonas aeruginosa: HS group 60 (38.0%); control group 69 (42.3%);

  2. Staphylococcus aureus: HS group 98 (62.0%); control group 124 (76.1%);

  3. MRSA: HS group 5 (3.2%); control group 11 (6.8%);

  4. Stenotrophomonas maltophilia: 25 (15.8%); 35 (21.5%);

  5. Achromobacter xylosoxidans: HS group 4 (2.5%); control group 3 (1.8%).
Interventions Pretreatment: all participants received albuterol or levalbuterol prior to each trial drug dose ‐ 2 puffs via MDI via a valved holding chamber with face mask or by nebulizer (distinct from the nebulizer used to administer the trial drug) and PARI Proneb® Ultra compressor.
Group 1 (n = 158): HS 7% 2x daily.
Group 2 (n = 163): IS 0.9% 2x daily.
Both treatments administered via Proneb Ultra compressor with a Sprint Jr nebulizer equipped with a Baby facemask or mouthpiece ‐ participants under 36 months used a facemask and those over 36 months used a mouthpiece, but this was individualized as developmentally appropriate.
Outcomes

  1. Pulmonary exacerbation rate (events per person‐year; defined as treatment with oral, inhaled, or intravenous antibiotics for 1 or more prespecified signs and symptoms)

  2. Number of treatment days and number of courses of antibiotics

  3. Time to first exacerbation

  4. Lung function (FEV 0.5, FEF 75, FEF25%-75%, FRC, RV/TLC)

  5. CFQ‐R (Quittner 2009) ‐ Parent and reported

  6. Change in height and weight

  7. Change in resting respiratory rate, pulse oximetry and parent‐reported cough

  8. Rate of intolerance to the test dose of HS at enrolment

  9. Adverse events and withdrawal rates

  10. Treatment‐emergent respiratory cultures positive for CF pathogens detected through clinical cultures performed at each site’s microbiology laboratory

  11. Adherence to treatment was assessed by 

    1. the number of used drug vials returned

    2. the Treatment Adherence Questionnaire completed quarterly

    3. the weekly parent questionnaire.
Notes Clinicaltrials.gov Identifier: NCT00709280.
Trial visits occurred at enrolment or randomization and 4, 12, 24, 36, and 48 weeks after randomization. At the enrolment visit, after pretreatment with albuterol or levalbuterol, all participants were evaluated for intolerance to a test dose of 7% HS according to predefined criteria. Participants who tolerated the test dose were randomized.
Sample size calculation was undertaken.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Participants were randomised 1:1 based on random permuted blocks, stratified by age and site (4 to 29 months, 30 to 60 months) via a secure website.
Allocation concealment (selection bias) Low risk Randomisation was done via a secure website.
Blinding of participants and personnel (performance bias)
All outcomes High risk HS (Hyper‐Sal; PARI Respiratory Equipment) and 0.9% IS supplied by Catalent Pharma Solutions as identically packaged 4 mL blow‐fill‐seal plastic ampoules, but taste could be discerned as different.
Blinding of outcome assessment (detection bias)
All outcomes Low risk Researchers blinded.
Incomplete outcome data (attrition bias)
All outcomes Low risk ITT analysis of 158 in HS group and 163 in control group. Details of withdrawals given as follows:
HS group: 15 withdrew in total (follow‐up range, 2 to 44 weeks): 5 lost to follow‐up; 4 treatment burden; 2 intolerant to trial drug; 1 time constraints; 3 other.
Control group: 14 withdrew in total (follow‐up range, 0 ‐ 42 weeks): 2 lost to follow‐up; 3 treatment burden; 2 insufficient perceived benefit from trial drug; 1 intolerant to trial drug; 1 time constraints; 1 other adverse event; 4 other.
Selective reporting (reporting bias) Low risk All outcomes stated in the methods were described in the results.
Other bias Low risk Sample size calculation was done. No other bias identified