Konstan 2020.
| Study characteristics | ||
| Methods | Phase III, international, multicentre, randomised, double‐blind, placebo‐controlled trial of ataluren in participants with nonsense mutation CF not receiving chronic inhaled aminoglycosides | |
| Participants | Participants recruited from 75 sites across 16 countries in North America, Europe and Australasia Inclusion criteria included (but were not limited to): age 6 years and over; sweat chloride > 60 mEq/L; demonstration of a FEV1 ≥ 40% and ≤ 90% of % predicted; and documentation of the presence of a nonsense mutation in at least 1 allele of the CFTR gene 279 participants were enrolled in the trial Age Treatment group: mean (SD) 22 (11); range 6 to 52 years Control group: mean (SD) 22 (10.7); range 6 to 52 years Age split by group Treatment group: under 18 years, 59 (42.1%); 18 years and over, 81 (57.9%) Control group: under 18 years, 56 (40.3%); 18 years and over, 83 (59.7%) Sex Treatment group: 81 (57.9%) males, 59 (42.1%) females Control group: 65 (46.8%) males, 74 (53.2%) females FEV1 %predicted at baseline Treatment group: mean (SD) 63.5 (13.46); range 40 to 88 Control group: mean (SD) 62.2 (14.34); range 40 to 90 Sweat chloride at baseline (mEq/L)b Treatment group: mean (SD) 100.7 (2.87); range 95 to 120 Control group: mean (SD) 100.0 (2.99); range 93 to 107 Inhaled antibiotic use at randomisation Total: treatment group 86 (61.4%). control group 66 (47.5%) Colistimethate: treatment group 60 (42.9%), control group 49 (35.3%) Aztreonam: treatment group 33 (23.6%). control group 22 (15.8%) Tobramycim: treatment group 0, control group 0 |
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| Interventions | Ataluren (PTC124) in oral powder for suspension form taken 3 times per day (10 mg/kg in the morning, 10 mg/kg at midday and 20 mg/kg in the evening) for 48 weeks Placebo |
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| Outcomes |
Primary outcome measure 1. FEV1 by spirometrya Secondary outcome measures 1. Rate of pulmonary exacerbations (modified Fuchs' criteria)a 2. Respiratory health‐related quality of life as assessed by the CFQ‐R respiratory domaina 3. Body weight and BMIa Other outcome measures 1. FVCa and FEF25-75 by spirometry 2. Incidence and duration of pulmonary exacerbationsa 3. Other health‐related quality of life domains as assessed by the CFQ‐Ra 4. Concentrations of liver enzyme tests (AST, ALT, GGT) 5. Faecal calprotectin level 6. New P aeruginosa lung infectiona 7. Safety profile characterised by type, frequency, severity, timing and relationship to study drug of treatment‐emergent adverse events, laboratory abnormalities and electrocardiogram abnormalitiesa 8. Trial drug compliance as assessed by quantification of unused trial drug 9. Trough ataluren plasma concentrations Timeframe for all outcomes measures stated to be 48 weeks |
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| Notes |
aThese outcomes are presented in the review. bmEq/L is equivalent to mmol/L. cTrial registry report states 88 sites, but published paper states 75. |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | The randomisation code was externally generated using a small block size (4), stratified by age (less than 18 years versus 18 years and older), chronic inhaled antibiotic use (yes versus no), and FEV1 % predicted (40% to less than 65% versus 65% to 90%). |
| Allocation concealment (selection bias) | Low risk | Interactive response technology was used to allocate participants to ataluren or placebo. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | All participants were blinded to treatment; the appearance of the placebo was described as identical, but details of the consistency and taste of the placebo have not been provided. We still judged this to result in a low risk of bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Only designated personnel at the contract research organisation had access to the treatment assignments; medical and ancillary staff, the trial investigators and the sponsor were blinded to treatment. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 279 participants were randomised: 140 participants to the ataluren group and 139 participants to the placebo group. 2 participants from the ataluren group and 3 from the placebo group were excluded prior to week 8 and were excluded from the ITT population. The ITT population included 138 participants in the ataluren group and 136 participants in the placebo group, and results were reported on the ITT population. A further 11 participants from each group withdrew after week 8 (meaning the total number of withdrawals was 13 from the ataluren group and 14 from the placebo group). At week 48, there were missing FEV1 data for 15 participants in the ataluren group and 21 participants in the placebo group. |
| Selective reporting (reporting bias) | Low risk | The protocol was available online and all outcomes listed in the protocol were reported. |
| Other bias | Low risk | Similar baseline characteristics and median rate of compliance (95% for ataluren and 95% for placebo). |
ALT: alanine aminotransferase AST: aspartate aminotransferase BMI: body mass index CF: cystic fibrosis CFQ‐R: cystic fibrosis questionnaire ‐ revised CFTR: cystic fibrosis transmembrane conductance regulator FEF25-75: mid expiratory flow FEV1: forced expiratory volume in one second FVC: forced vital capacity GGT: gamma‐glutamyl transpeptidase ITT: intention to treat RCT: randomised controlled trial SD: standard deviation