Methods

Randomized, double‐blinded, placebo‐controlled, 3‐month dose escalation study in children with CF.
Randomized to ibuprofen or placebo in a ratio of 2:1.
Computer‐generated random code.

Participants

19 children with CF aged 6‐12 years.
Inclusion criteria ‐ diagnosed clinically and by sweat test, aged 6‐12 years. Eligible if FEV₁ > 30% predicted for age, height and gender; judged to be clinically stable; no history of adverse effects with aspirin, ibuprofen or other NSAID; not taking 'interfering medication' (not defined).
13 (7 male) in treatment group and 6 (3 male) in placebo group. 1 female in placebo group dropped out on day 1 because of difficulty with venous access.

Interventions

3‐month dose escalation study.

Participants received 300 mg ibuprofen orally and twice daily during the first month, and, depending on pharmacokinetic studies, 400 mg in the second month, and 600 mg in the third month.

Control ‐ placebo.

Outcomes

Compliance.
Number to complete.
Dropout rates.
Number hospital admissions for exacerbations.
Number hospital days for exacerbations.
Percentage predicted FEV₁.
Adverse events e.g. abdominal pain, occult blood, change in number of stools and epistaxis.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate, randomisation was based upon a computer‐generated randomisation sequence.

Allocation concealment (selection bias)

Low risk

Adequate, the randomisation sequence was provided by the pharmaceutical company (Upjohn).

Blinding (performance bias and detection bias)
All outcomes

Low risk

Described as double blinded. The pharmaceutical company provided the clinics with identical‐appearing placebo tablets.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Less than 15% of participants excluded (three participants) due to poor venous access, behavioural problems and difficulty in transport to follow up trial visits.

Selective reporting (reporting bias)

High risk

Outcomes listed were reported, but the trial investigators monitored a large number of potential adverse effects of ibuprofen: reporting was confined to those considered to be most important and findings which were not statistically significant were not reported

Other bias

Unclear risk

Reported adverse events.

Methods

Randomized double‐blinded, placebo‐controlled study.
Permuted blocks of 4 participants stratified by age.
Randomization code was known only by the pharmacologist and the pharmacist.

Participants

85 people with CF aged 5‐39 years.
Inclusion criteria ‐ people with CF, diagnosed clinically and by sweat test, not treated with intravenous antibiotics in preceding 2 months and with FEV₁ at least 60% predicted.
42 (26 male) were in the treatment group and 43 (15 male) in placebo group; age range 5‐39 years.
Exclusion criteria: systemic or inhaled corticosteroids used within two years of recruitment or inhaled sodium cromoglycate used within 6 months of recruitment.

A total of 28 participants withdrew from study, with similar numbers in both groups (15 in treatment group, 13 in placebo group).

Interventions

Participants randomly assigned to receive high‐dose oral ibuprofen twice daily for 4 years or placebo twice daily for 4 years. Dose 20‐30 mg per kg of body weight, to a maximum of 1600 mg, determined by pharmacokinetic analyses.

Outcomes

Compliance (pill counts and blood monitoring)
Number to complete
Dropout rates
Number hospital admissions for exacerbations
Number hospital days for exacerbations
Annual rate of change in FEV₁, FVC, FEF_25‐75%
Percentage predicted FEV₁, FVC, FEF_25‐75
Annual rate of change in percentage ideal body weight
Change in Brasfield chest X‐ray score over 4‐year period
Intravenous antibiotics administered at home
Adverse events e.g. abdominal pain, conjunctivitis, epistaxis
Concomitant therapy

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate, randomisation was carried out with permuted blocks of four participants each stratified by age (under 13 years, 13 to 18 years and 19 years or over).

Allocation concealment (selection bias)

Low risk

Adequate, paper states that only the pharmacologist and pharmacist were privy to the allocation.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Described as double blinded. The placebo tablets were identical in appearance to the ibuprofen tablets.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Analysis was based on intention‐to‐treat.

A total of 28 participants withdrew from study, with similar numbers in both groups (15 in treatment group, 13 in placebo group).

Selective reporting (reporting bias)

High risk

Outcomes listed were reported, but the trial investigators monitored a large number of potential adverse effects of ibuprofen: reporting was confined to those considered to be most important and findings which were not statistically significant were not reported

Other bias

Unclear risk

Intention‐to‐treat and completed treatment analysis are presented, intention‐to‐treat analysis was only used in the meta‐analysis.

Reported adverse events.

Funded by the Cystic Fibrosis Foundation and the National Institutes of Health.

Methods

Multicenter double‐blind placebo‐controlled trial.
Allocated treatment by a centralized pharmacy using a pre‐defined block randomization schedule.

Participants

142 children with CF aged 6‐18 years.
Inclusion criteria: FEV₁ >60% predicted at time of entry into the trial, with no hospitalizations in the previous 2 months.
Exclusion criteria: people who had taken systemic corticosteroids or non‐steroidal anti‐inflammatory agents for more than 1 month in the past year, had abnormal hepatic, renal, hematologic disorders or coagulopathy, documented evidence of peptic ulcer disease(endoscopy) or allergic bronchopulmonary aspergillosis, or a history of hypersensitivity reactions to non‐steroidal anti‐inflammatory agents.

18 participants (9 in each group) did not complete full 2 years of follow up, 11 due to adverse events (4 in treatment group, 7 in placebo group).

Interventions

All participants underwent a baseline pharmacokinetic study (baseline every hour for 3 hours), employing 200 mg tablets (Upjohn‐Pharmacia) at a dose of 20 to 30 mg/kg to a maximum of 1600 mg. The number of assigned pills were then adjusted by the coordinating pharmacologist to provide a peak plasma concentration of 50 to 100 microg/ml for each participant in the study. Participants then were asked to take the prescribed number of pills (ibuprofen or placebo) twice daily.

Outcomes

Annual rate of change in FEV₁ % predicted, FVC % predicted, anthropometric data, chest radiograph score, number of hospitalizations (and length of stay), adverse effects, compliance, concomitant therapy(antibiotics, inhaled anti‐inflammatory agents).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Adequate, participants were allocated using a predefined block‐randomisation schedule.

Allocation concealment (selection bias)

Low risk

Adequate, a central pharmacy coded and shipped the tablets to the participating centers; the code was broken by the central pharmacy only on request from the Safety and Monitoring Committee.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Described as double blinded. Paper states that participants, care‐givers and study personnel were all blinded to treatment assignment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Analysis was based on intention‐to‐treat.

18 participants (9 in each group) did not complete full 2 years of follow up, 11 due to adverse events (4 in treatment group, 7 in placebo group); details of these events in paper.

Selective reporting (reporting bias)

Low risk

Outcomes listed were reported.

Other bias

Unclear risk

Reported adverse events.

Funders did not have a role in the analysis or publication of results.

Methods

Randomized, double‐blinded, placebo‐controlled study of piroxicam or placebo.
Participants distributed into 2 balanced groups according to sex, age and Shwachman score.
Allocation concealment and generation of the allocation sequence unclear.

Participants

41 people with CF aged 5 ‐ 37 years.
Inclusion criteria: people with CF, diagnosed by sweat test and clinically, and regularly attending the CF clinic at the Children's Hospital in Buenos Aires.
Participants were aged 5 ‐ 37 years and 20 (10 male) were randomized to active treatment with piroxicam and 21 (11 male) to treatment with placebo.

Interventions

Doses were according to participants' body weight: <15 kg: 5 mg/day; 16‐25 kg: 10 mg/day; 26‐45 kg: 15 mg/day and >46 kg: 20 mg/day. Piroxicam and placebo were taken by the participants in a single morning dose. Treatment was suspended during periods of hospitalization and reinstated after discharge. Participants for whom treatment was suspended for more than 30 days were removed from the trial.

Outcomes

Dropout rates.
Deaths.
Number of hospital admissions.
Number of hospital days.
Number of participants admitted.
Increase in abdominal pain.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Process was described as random in the paper, but the randomisation method was not described.

Allocation concealment (selection bias)

Unclear risk

Unclear, concealment of allocation was not discussed.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Described as double blinded. Paper describes the placebo tablets as being "indistinguishable" from the piroxicam tablets.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

More than 15% of participants were excluded from the intention‐to‐treat analysis (n = 8) (Sordelli 1994). Four participants from the treatment group and four from the control group did not complete the study. Reasons for exclusion included abdominal pain, hematemesis, hepatic dysfunction and acute respiratory exacerbation.

Selective reporting (reporting bias)

Low risk

Outcomes listed were reported.

Other bias

Unclear risk

Reported adverse events.