Background
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.