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

Review question

How does ivacaftor affect clinical outcomes (survival, quality of life and lung function) in people with cystic fibrosis (CF)?

Background

In people with CF, airway surfaces do not have enough water because of an abnormal protein; this makes it difficult to clear thick and sticky mucus, which leads to lung infections. Ivacaftor works on the abnormal protein in people with some mutations to allow the airways retain more water and better clear mucus, so fewer lung infections develop.

Ivacaftor was aimed at people with class III and IV mutations, and has been studied in people with G551D (class III), R117H (class IV) and F508del (class II) mutations.

Trial characteristics

We included five trials (447 participants) comparing ivacaftor to placebo (dummy treatment with no active medication) lasting between four and 48 weeks. Three trials enrolled a total of 238 people with at least one copy of the G551D mutation, one trial enrolled 140 people with two copies of the F508del mutation and one enrolled 69 people with at least one copy of the R117H mutation. The evidence is up to date as of 21 November 2018.

Key results

F508del mutation

The trial did not report any deaths or show improvements in lung function, quality of life scores or weight. Cough and pulmonary exacerbations (flare ups of lung disease) were the most reported adverse events when taking both ivacaftor and placebo; there were a similar number of flare ups for both groups. Sweat chloride concentrations were reduced with ivacaftor.

G551D mutation

No deaths were reported. Both children and adults taking ivacaftor showed improvements in lung function, but only adults reported higher quality of life scores. People given placebo reported more coughing and experienced more episodes of decreased lung function; more adults taking ivacaftor reported episodes of dizziness. Similar numbers of people taking ivacaftor and placebo delayed the course of medication, or withdrew from the trial altogether, due to side effects (e.g. psychological issues, liver disease, severe breathing problems). There were more serious pulmonary exacerbations whilst taking placebo compared to ivacaftor. Adults taking ivacaftor were admitted to hospital less often and had fewer courses of intravenous antibiotics for exacerbations. Both children and adults and children increased their weight with ivacaftor. There was a drop in sweat chloride concentrations with ivacaftor.

R117H mutation

No deaths occurred in this trial. While quality of life scores improved with ivacaftor, lung function did not. Cough and pulmonary exacerbations (flare ups of lung disease) were the most reported adverse events when taking both ivacaftor and placebo; there were a similar number of flare ups for both groups. There was no difference in weight; but as for other mutations there was a reduction in sweat chloride concentration with ivacaftor.

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 F508del or R117H mutations.

Quality of the evidence

In most trials, individuals were put into different treatment groups at random with equal chances of being given either placebo or ivacaftor; no one could work out which treatment the next person would receive, so that healthier people did not receive ivacaftor and make the results seem better. We were not sure whether anyone involved in the trial knew who was receiving which treatment and how this might affect results. No trials reported all 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 our certainty regarding the overall results. Information about some side effects was limited as not many people experienced them, therefore, it is difficult to judge whether there was a difference between treatment groups

We judged the evidence in this review to be moderate to low quality.

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: 

There is no evidence supporting the use of ivacaftor in people with the F508del mutation. Both G551D phase 3 trials demonstrated a clinically relevant impact of ivacaftor on outcomes at 24 and 48 weeks in adults and children (over six years of age) with CF. The R117H trial demonstrated an improvement in the respiratory QoL score, but no improvement in respiratory function.

As new mutation-specific therapies emerge, it is important that trials examine outcomes relevant to people with CF and their families and that adverse events are reported robustly and consistently. Post-market surveillance is essential and ongoing health economic evaluations are required.

Read the full abstract...
Background: 

Cystic fibrosis (CF) is the commonest inherited life-shortening illness in white populations, 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 mainly affects the airways where excess salt absorption dehydrates the airway lining leading to impaired mucociliary clearance. Consequently, thick, sticky mucus accumulates making the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Other complications include malnutrition, diabetes and subfertility.

Increased understanding of the condition has allowed pharmaceutical companies to design mutation-specific therapies targeting the underlying molecular defect. CFTR potentiators target mutation classes III and IV and aim to normalise airway surface liquid and mucociliary clearance, which in turn impacts on the chronic infection and inflammation. This is an update of a previously published review.

Objectives: 

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

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, reviews and online clinical trial registries. Last search: 21 November 2018.

Selection criteria: 

Randomised controlled trials (RCTs) of parallel design comparing CFTR potentiators to placebo in people with CF. A separate review examines trials combining CFTR potentiators with other mutation-specific therapies.

Data collection and analysis: 

The authors independently extracted data, assessed the risk of bias in included trials and used GRADE to assess evidence quality. Trial authors were contacted for additional data.

Main results: 

We included five RCTs (447 participants with different mutations) lasting from 28 days to 48 weeks, all assessing the CFTR potentiator ivacaftor. The quality of the evidence was moderate to low, mainly due to risk of bias (incomplete outcome data and selective reporting) and imprecision of results, particularly where few individuals experienced adverse events. Trial design was generally well-documented. All trials were industry-sponsored and supported by other non-pharmaceutical funding bodies.

F508del (class II) (140 participants)

One 16-week trial reported no deaths, or changes in quality of life (QoL) or lung function (either relative or absolute change in forced expiratory volume in one second (FEV1) (moderate-quality evidence). Pulmonary exacerbations and cough were the most reported adverse events in ivacaftor and placebo groups, but there was no difference between groups (low-quality evidence); there was also no difference between groups in participants interrupting or discontinuing treatment (low-quality evidence). Number of days until the first exacerbation was not reported, but there was no difference between groups in how many participants developed pulmonary exacerbations. There was also no difference in weight. Sweat chloride concentration decreased, mean difference (MD) -2.90 mmol/L (95% confidence interval (CI) -5.60 to -0.20).

G551D (class III) (238 participants)

The 28-day phase 2 trial (19 participants) and two 48-week phase 3 trials (adult trial (167 adults), paediatric trial (52 children)) reported no deaths. QoL scores (respiratory domain) were higher with ivacaftor in the adult trial at 24 weeks, MD 8.10 (95% CI 4.77 to 11.43) and 48 weeks, MD 8.60 (95% CI 5.27 to 11.93 (moderate-quality evidence). The adult trial reported a higher relative change in FEV1 with ivacaftor at 24 weeks, MD 16.90% (95% CI 13.60 to 20.20) and 48 weeks, MD 16.80% (95% CI 13.50 to 20.10); the paediatric trial reported this at 24 weeks, MD 17.4% (P < 0.0001)) (moderate-quality evidence). These trials demonstrated absolute improvements in FEV1 (% predicted) at 24 weeks, MD 10.80% (95% CI 8.91 to 12.69) and 48 weeks, MD 10.44% (95% CI 8.56 to 12.32). The phase 3 trials reported increased cough, odds ratio (OR) 0.57 (95% CI 0.33 to 1.00) and episodes of decreased pulmonary function, OR 0.29 (95% CI 0.10 to 0.82) in the placebo group; ivacaftor led to increased dizziness in adults, OR 10.55 (95% CI 1.32 to 84.47). There was no difference between groups in participants interrupting or discontinuing treatment (low-quality evidence). Fewer participants taking ivacaftor developed serious pulmonary exacerbations; adults taking ivacaftor developed fewer exacerbations (serious or not), OR 0.54 (95% CI 0.29 to 1.01). A higher proportion of participants were exacerbation-free at 24 weeks with ivacaftor (moderate-quality evidence). Ivacaftor led to a greater absolute change from baseline in FEV1 (% predicted) at 24 weeks, MD 10.80% (95% CI 8.91 to 12.69) and 48 weeks, MD 10.44% (95% CI 8.56 to 12.32); weight also increased at 24 weeks, MD 2.37 kg (95% CI 1.68 to 3.06) and 48 weeks, MD 2.75 kg (95% CI 1.74 to 3.75). Sweat chloride concentration decreased at 24 weeks, MD -48.98 mmol/L (95% CI -52.07 to -45.89) and 48 weeks, MD -49.03 mmol/L (95% CI -52.11 to -45.94).

R117H (class IV) (69 participants)

One 24-week trial reported no deaths. QoL scores (respiratory domain) were higher with ivacaftor at 24 weeks, MD 8.40 (95% CI 2.17 to 14.63), but no relative changes in lung function were reported (moderate-quality evidence). Pulmonary exacerbations and cough were the most reported adverse events in both groups, but there was no difference between groups; there was no difference between groups in participants interrupting or discontinuing treatment (low-quality evidence). Number of days until the first exacerbation was not reported, but there was no difference between groups in how many participants developed pulmonary exacerbations. No changes in absolute change in FEV1 or weight were reported. Sweat chloride concentration decreased, MD -24.00 mmol/L (CI 95% -24.69 to -23.31).

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