Ivacaftor (marketed as Kalydeco®), a new specific therapy for cystic fibrosis

Review Question

What is the effect of ivacaftor on clinical outcomes (survival, quality of life and lung function) in people with cystic fibrosis?


In people with cystic fibrosis, airway surfaces don't have enough water due to the action of an abnormal protein. This makes it difficult to clear thick and sticky mucus and leads to these people developing lung infections. Ivacaftor works on the abnormal protein in people with certain cystic fibrosis mutations (class III and IV) such as the G551D mutation (class III). It aims to help the airways retain more water allowing them to clear mucus more effectively, so these people develop fewer lung infections. The drug may also affect other classes of mutation and there are trials currently being run to look at this.

Ivacaftor was aimed at people with class III and IV mutations, but up to now it has only been studied in those with the G551D (class III) and ΔF508 (class II) mutations.

Trial Characteristics

We included four trials (378 volunteers) comparing ivacaftor to placebo (a dummy treatment with no active medication). Three trials enrolled 238 volunteers between them with at least one copy of the G551D mutation; one trial enrolled 140 volunteers with two copies of the ΔF508 mutation (class II). The trials lasted between 4 and 48 weeks. The evidence is up to date as of 05 March 2015.

Key Results

None of the trials reported any deaths. Both children and adults with the G551D mutation taking ivacaftor showed improvements in lung function (forced expiratory volume at one second), but only the adults reported higher quality of life scores. Participants with the ΔF508 mutation did not show improvements in either of these outcomes.

Volunteers with the G551D mutation in the placebo groups reported more coughing and experienced more episodes of decreased pulmonary function. More adults taking ivacaftor reported episodes of dizziness. Similar small numbers of volunteers (both mutations) taking ivacaftor and placebo had to delay the course of medication, or withdraw from the trial altogether, due to unfavourable side effects (e.g. psychological issues, liver disease, severe breathing problems, fatigue, arthritis).

More children and adults with the G551D mutation experienced serious pulmonary exacerbations (flare ups of their lung disease) whilst taking placebo. More adults taking placebo developed these lung flare ups than those taking ivacaftor. Adults taking ivacaftor were admitted to hospital less often and had fewer courses of intravenous antibiotics for flare ups. People with the ΔF508 mutation, had a similar number of flare ups whether taking placebo or ivacaftor.

Adults and children with the G551D mutation taking ivacaftor increased their weight; but not those with ΔF508.

Evidence suggests that ivacaftor is an effective treatment for people (over six years of age) with cystic fibrosis and the G551D mutation, but not for those with the ΔF508 mutation. Trials of ivacaftor in people with different genetic mutations are underway.

Quality of the evidence

In most of the trials, the volunteers were put into different treatment groups completely at random, so we were satisfied that those taking part had an equal chance of being in either group (placebo or ivacaftor). We are also satisfied that in most trials no one could work out which group the next volunteer would be put into, so that healthier people did not receive the treatment and make the results seem better. We could not be sure whether the people taking part in the trial or the clinicians running the trial knew who was receiving which treatments and what effect this knowledge might have on the results. Unfortunately, none of the trials reported all their results clearly; sometimes they did not report them in a way that we could use in the review and sometimes they did not report the data at all. This affected the certainty with which we judged the overall results.

Trial Funding Sources

All trials were sponsored by Vertex Pharmaceuticals Incorporated. The National Institute of Health (NIH), the Cystic Fibrosis Foundation (CFF) and other non-pharmaceutical funding bodies also supported the trials.

Authors' conclusions: 

Both G551D phase 3 trials (n = 219) demonstrated a clinically relevant impact of the potentiator ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of this treatment in adults and children (over six years of age) with cystic fibrosis and the G551D mutation (class III). There is no evidence to support the use of ivacaftor in people with the ΔF508 mutation (class II) (n = 140). Trials on ivacaftor in people with different mutations are ongoing.

Read the full abstract...

Cystic fibrosis is the most common inherited life-shortening illness in Caucasians and caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation most notably affects the airways of people with cystic fibrosis. Excess salt absorption by defective CFTR dehydrates the airway lining and leads to defective mucociliary clearance. Consequent accumulation of thick, sticky mucus makes the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Additionally, abnormalities with CFTR lead to systemic complications like malnutrition, diabetes and subfertility.

Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation-specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re-establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations.


To evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis.

Search strategy: 

We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Last search: 05 March 2015.

We searched the EU Clinical Trials Register, clinicaltrials.gov (US Clinical Trials Register) and the International Clinical Trials Registry Platform (ICTRP). Last search of clinical trial registries: 06 February 2014.

Selection criteria: 

Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation-specific therapies. These will be considered in a separate review.

Data collection and analysis: 

The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at a number of time points.

Main results: 

We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta-analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II).

Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non-pharmaceutical funding bodies.

No trial reported any deaths. Significantly higher quality of life scores in the respiratory domain were reported by the adult phase 3 G551D trial at 24 weeks, mean difference 8.10 (95% confidence interval (CI) 4.77 to 11.43) and 48 weeks, mean difference 8.60 (95% CI 5.27 to 11.93); but not by the paediatric phase 3 G551D trial. The adult phase 3 G551D trial reported improvements in relative change from baseline in forced expiratory volume at one second at 24 weeks, mean difference 16.90% (95% CI 13.60 to 20.20) and 48 weeks, mean difference 16.80% (95% CI 13.50 to 20.10); as did the paediatric G551D trial at 24 weeks, mean difference 17.4% (P < 0.0001)). No improvements in quality of life or lung function were reported in the ΔF508 participants.

Combined data from both phase 3 G551D trials demonstrated increased reporting of cough, odds ratio 0.57 (95% CI 0.33 to 1.00) and increased episodes of decreased pulmonary function, odds ratio 0.29 (95% CI 0.10 to 0.82) in the placebo group. The adult phase 3 G551D trial demonstrated increased reporting of dizziness amongst the ivacaftor group, OR 10.55 (95% CI 1.32 to 84.47). No trial showed a difference between treatment arms in the number of participants interrupting or discontinuing the trial drug.

In the phase 3 G551D trials, fewer participants assigned to ivacaftor developed serious pulmonary exacerbations. When considering all data for exacerbations, participants taking ivacaftor in the adult phase 3 G551D study developed fewer exacerbations, odds ratio 0.54 (95% CI 0.29 to 1.01). In the other G551D studies and in the ΔF508 study, there was no difference between groups in the number of participants who developed pulmonary exacerbations.

Combined data from both phase 3 G551D trials demonstrated significant improvements in absolute change from baseline in forced expiratory volume at one second (% predicted) at 24 weeks, mean difference 10.80% (95% CI 8.91 to 12.69) and 48 weeks, mean difference 10.44% (95% CI 8.56 to 12.32); also in weight at 24 weeks, mean difference 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, mean difference 2.75 kg (95% CI 1.74 to 3.75). No improvements in these outcomes were reported in the ΔF508 participants.

Significant reductions in sweat chloride concentration were reported in both G551D and ΔF508 participants: in combined data from both phase 3 G551D trials at 24 weeks, mean difference -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, mean difference -49.03 mmol/L (95% CI -52.11 to -45.94); and from the ΔF508 trial at 16 weeks, mean difference -2.90 mmol/L (95% CI -5.60 to -0.20).