American Journal of Respiratory and Critical Care Medicine

The recent announcement of the negative results of the TIGER-2 phase 3 study of denufosol tetrasodium (Denufosol; Inspire Pharmaceuticals, Chapel Hill, NC) has had a considerable impact on the cystic fibrosis (CF) community, researchers, and industry. Denufosol is a novel ion channel regulator that theoretically can correct ion transport in patients independent of the class of CF transmembrane conductance regulator (CFTR) defect. Denufosol is designed to enhance airway hydration and mucociliary clearance by increasing chloride secretion, inhibiting sodium absorption, and increasing ciliary beat frequency (1, 2).

Denufosol is one of a group of new agents that include CFTR potentiators and correctors undergoing phase III evaluation that hold the promise of CF disease modification. By improving hydration of the airway surface liquid and mucous clearance, Denufosol has the potential to prevent lung disease that results from airway dehydration, inflammation, and infection and ultimately to prevent bronchiectasis if commenced early in life.

Denufosol showed great promise in early studies. The TIGER-1 trial was a 24-week randomized, placebo-controlled study of 60 mg of denufosol administered three times daily in 352 patients at least 5 years of age with mild CF lung disease (FEV1, ≥ 75% of predicted) followed by a 24-week open-label safety extension (3). The TIGER-1 trial demonstrated statistical significance for its primary efficacy endpoint of change in FEV1 from baseline compared with placebo at the Week 24 endpoint (45 ml treatment group difference, P = 0.047).

However, in TIGER-2, a randomized, double-blind, placebo-controlled, parallel-group, study in patients at least 5 years of age with FEV1 greater than or equal to 75% predicted, Denufosol was not superior to placebo for the primary efficacy endpoint (change from baseline in FEV1) or secondary outcome measures (rate of change in percent predicted FEV1, change from baseline in FEF25%–75%, and time to first pulmonary exacerbation).

The choice of patient population was intended to include individuals with mild disease to capture changes in the primary outcome measure that would indicate the potential for the intervention to modify lung disease. However, recent studies have clearly indicated that the pathobiologic features of CF (airway inflammation, infection, and structural lung disease) occur early and are well established at the age at which patients could be entered into the TIGER-2 study.

Data from the Australian Early Surveillance Team for CF (AREST CF) and others have convincingly demonstrated that bronchiectasis, the major cause of morbidity and mortality in CF, can be present soon after diagnosis (48), even in asymptomatic infants identified by newborn screening (79). Furthermore, the prevalence and extent of structural changes detected using low-dose computed tomography (CT) increases with age and are associated with indicators of neutrophilic inflammation (8).

The population most likely to benefit from intervention with disease-modifying therapies is newly diagnosed children with CF. There is a clear window of opportunity, in the first 6 months of life, when lung damage is minimal and lung function is normal (8, 10). However, for regulatory purposes the Federal Drug Administration (FDA) only accepts FEV1, patient-reported symptoms, and exacerbations as outcome measures for intervention studies in CF. These are poor surrogates for structural lung disease (11), and of these only exacerbations can be measured in infants. Therefore, currently, new therapies cannot be subject to clinical testing in infants using protocols that would meet the criteria for FDA approval.

The issues regarding outcome measures and clinical trials in infants and young children are complex (12). However, chest computed tomography (CT) appears to best reflect structural lung disease in patients with CF at all ages and all levels of disease severity (5, 8, 1315). CT is probably the most direct technique to demonstrate lung disease other than lung biopsy. Techniques are available that can achieve high-resolution images in inspiration and expiration that expose children to 1 mSv radiation or less in total. Furthermore, the most recent evidence from the AREST CF collaboration indicates that despite best available tertiary care, bronchiectasis detected by CT is persistent or progressive in the majority of infants and preschool children with CF and is associated with endobronchial infection and inflammation (16). Based on these data the COMBAT CF randomized, placebo-controlled study ( identifier NCT01270074) funded by US CF Foundation Therapeutics, Inc., and supported by Pfizer (New York, NY) will investigate whether azithromycin from diagnosis will reduce the prevalence of CT-detected bronchiectasis at age 3 years. This is the first study in a newborn-screened population to determine whether an early intervention can prevent structural lung disease, and the first to use chest CT as a trial endpoint in such a population.

The assertion that Denufosol and other pipeline therapies are potentially disease modifying implies that these interventions should prevent the onset and slow the development of structural lung disease. We believe that in the case of Denufosol, this fundamental hypothesis has yet to be adequately tested. Furthermore, we are concerned that clinical trials of other medications with disease-modifying potential might also fail to address this critical question due to limitations in trial design, primarily imposed by regulatory requirements and because of nervousness on the part of industry and investors regarding trials in young children. We have recently argued (17) that a different approach is needed for primary prevention studies. Such studies must, by their very nature, start in early life, where the effect size is likely to be small and where short-term outcomes with long-term prognostic implications are required. We believe that to discard therapies that fail to meet significance for outcomes that are not relevant to young children who could otherwise be expected to obtain significant benefit is unethical. Therefore, strategies need to be developed to ensure that trials of agents with disease-modifying capability are undertaken in young children with CF early in the development and regulatory cycle rather than as an afterthought. This will require collaboration between industry, research funding bodies, and regulatory agencies to ensure that mechanisms exist to support such studies.

We suggest that the COMBAT CF trial design could be used as a template for randomized, controlled studies in infants and preschool children, and urge regulatory agencies to consider the utility of chest CT as a trial endpoint in young children with CF. The availability of chest CT and recent developments in lung function testing such as the lung clearance index (18, 19) indicate that in the future, young children with CF should not be excluded from efficacy studies of new therapies that claim to be disease modifying. However, since many of the anticipated outcome measures, such as CT and infant pulmonary functioning, have inherent (albeit small) risks, these need to be carefully evaluated in the design of future intervention studies for which they are used.

Progress in childhood outcomes has accounted for most of the improvements in median survival and adult lung function in CF. Although there have been continuous improvements in lung function in adolescents and young adults, the rate of decline in lung function and the mortality rate have remained similar in adults for several decades (20). Disease-modifying agents commenced early in life and that prevent lung disease are clearly going to be important for improving outcomes in CF. However, current regulatory requirements around acceptable trial outcomes effectively exclude the group of patients most likely to benefit from clinical trials of efficacy. This state of affairs discriminates against young children with CF and does not serve well the CF community, pharmaceutical industry, or potential investors in CF research. We must do better for our patients!

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