Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial

Chronic obstructive pulmonary disease (COPD) clinical trials evaluating relatively infrequent endpoints such as mortality, respiratory failure, and/or hospitalized exacerbations are, of necessity, often large and require follow-up of patients over prolonged periods of time [1‐3]. Indeed, recent trials evaluating mortality as the outcome, such as the Tiotropium Safety and Performance in Respimat® (TIOSPIR®) study [3] or the Study to Understand Mortality and Morbidity in COPD (SUMMIT) [4], recruited more than 16,000 patients in order to have sufficient power to determine the significance of the outcomes.

Facing a similar situation, studies in other medically relevant fields have integrated infrequently occurring events into composite endpoints that have proven relevant to the planning of clinical trials and the likely benefit of treatment to patients [5‐9]. This is particularly relevant in the field of cardiology, where a composite measure of major adverse cardiac events (MACE) has become a frequent endpoint for therapeutic trials [5, 6, 10]. Composite endpoints have also been used in infectious diseases (including tuberculosis [7]), in stroke [11], collagen vascular disease [12], multiple sclerosis [9], diabetes [8], and renal failure [6]. In COPD, a composite endpoint for safety in an endobronchial valve trial for emphysema was evaluated [13].

Using data from a large-scale clinical trial in patients with moderate to very severe COPD [2], we explored three hypotheses. First, that four important individual outcomes in COPD—death, hospitalized exacerbations, respiratory failure, and withdrawal from the study due to worsening COPD—could be integrated into a composite endpoint. Second, that there are measurable differences in the composite endpoint incidence between an active and a control arm. And third, that based on these results, fewer patients would need to be recruited to achieve sufficient power to explore significant effects of interventions on these outcomes. These hypotheses were tested using data from the UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) trial, which included patients with COPD who were permitted to continue using their usual COPD medications, except for other inhaled anticholinergics [2].

UPLIFT® (ClinicalTrials.gov number, NCT00144339) was an international, multicenter, 4-year, randomized, placebo-controlled trial of tiotropium in patients with COPD, the details of which were previously published [2, 14, 15]. Patients were recruited from 490 centers in 37 countries. In brief, patients were aged ≥40 years, with a smoking history of ≥10 pack-years, postbronchodilator forced expiratory volume in 1 s (FEV₁) of ≤70 % of predicted, and FEV₁ to forced vital capacity (FVC) ratio of <0.70 of predicted. Exclusion criteria included a history of asthma, COPD exacerbation, or respiratory infection within 4 weeks of screening, prior pulmonary resection, and use of supplemental oxygen for >12 h/day. Using centralized randomization by country and by site, patients were randomized to 18 μg tiotropium or placebo (control) (once daily). All respiratory medications, with the exception of other inhaled anticholinergics, were permitted throughout the trial. Postrandomization clinic visits occurred at 1 month, at 3 months, and every 3 months throughout the 4-year treatment period. All patients gave written informed consent and the study was approved by local ethical review boards and conducted in accordance with the Declaration of Helsinki.

This analysis of data obtained in UPLIFT® yielded three important findings. First, a COPD composite endpoint incorporating infrequent serious or significant COPD-related safety outcomes can be useful to demonstrate efficacy and safety in clinical trials. Second, in the UPLIFT® trial, the IRs of CERO events were significantly reduced in patients receiving tiotropium compared with placebo [2]. Third, this approach may help plan studies incorporating efficacy and safety evaluation with a reasonable sample size and shorter time.

Randomized clinical trials represent the gold standard to evaluate the comparative efficacy and safety of novel therapies, especially pharmacological drugs. For highly prevalent and deadly diseases, potential therapies should be evaluated by their impact on important clinical endpoints. An example is COPD, a disease that constitutes one of the top four causes of death in the world and that in its more severe cases results in hospital admissions, which increase personal and societal costs. However, although COPD causes many deaths because of its high prevalence, its long natural course, and the relatively low incidence of deaths or hospitalized exacerbations has resulted in the need to complete studies with very large numbers of patients and over a long period. Thus, the TORCH (Towards a Revolution in COPD Health) and the UPLIFT® studies, which recruited ~6000 patients each, lasted 3 and 4 years, respectively; and the mortality and hospitalization rate signals were relatively weak [1, 2]. Based on those results, two other trials (TIOSPIR® and SUMMIT) evaluating mortality as an outcome needed to recruit more than 16,000 patients each to have sufficient power to address the impact of these interventions on mortality and hospitalized exacerbations [3, 4]. An alternative approach used in other fields with a high burden of disease that may be divided into several outcomes that by themselves are relatively rare has been integrating important clinical outcomes into a composite endpoint that can then represent a more comprehensive measure of the overall response to therapy from a safety perspective. Although most studies have been done in the general field of cardiology [10, 13, 15, 18, 19], there have been many reports of trials using composite endpoints in infectious diseases (including tuberculosis [7]) as well as in stroke [11], diabetes [8], rheumatoid arthritis [20], and renal failure [6], among others. Only one study used a composite endpoint to evaluate the safety of endobronchial valves [13]. Interestingly, some COPD studies used the composite endpoint MACE as a safety composite endpoint, but this was done to evaluate cardiac safety in COPD patients [2, 3, 21‐23].

We selected four hard endpoints because of their clinical validity and registered accuracy in this regard; we not only included all-cause mortality (an accepted patient-centered outcome), but also hospitalizations for exacerbations of COPD and respiratory failure. We considered that these latter two outcomes were appropriately associated with all-cause mortality to add strength to the observed results. Similarly, we included discontinuation from the study due to COPD worsening because this event in long clinical trials represents an important signal of decompensation of the target organ and relates to the patients’ own feelings regarding their deteriorating health [24]. We integrated all of the outcomes into the CERO and explored its value in the UPLIFT® study database.

The results of the study indicate a significant effect on the composite index that was of only borderline significance for the individual outcome of mortality in the original report [2]. Indeed, in this regard, neither UPLIFT® nor the TORCH trial has been considered as having shown a significant impact on mortality using mortality including vital status follow-up of discontinued patients [1, 2]. Several authors have criticized the use of composite endpoints when there are contradictions among the results for the individual components and when they are not clearly defined. This is not the case in the current study. As seen in Tables 2 and 3, the tiotropium arm showed a significant impact on the incident rate ratio for CERO compared with placebo, and the RRs for each of the individual components supported the beneficial effect. Further, the results were applicable across a wide range of airflow obstruction (Table 4), supporting general application of the results, at least for patients meeting the criteria for inclusion in UPLIFT®.

Perhaps the most important information provided by the current study is the power calculation of the number of subjects and the duration of the trial needed to obtain a significant result for a therapeutic intervention. Again, using the results from UPLIFT® and the composite measure of CERO, significant reduction in the social and economic cost of completing such trials is theoretically possible.

Using the IRs and RRs as the expected outcome, the sample sizes are certainly much smaller than the SUMMIT trial (16,000 patients) and the completed TIOSPIR® (17,135 patients) study, in which all-cause mortality was the primary endpoint. As the number of medications approved for the treatment of COPD and the benefits that are reported to support their routine use increase, ethical reasons will preclude the completion of long-term trials with a placebo-control arm. Thus, comparison trials may prove to be the way of the future, and the larger signals from composite endpoints a potentially useful tool to evaluate the results of those trials.

We recognize limitations to this study. First, it is a retrospective analysis of data collected for a study in which the primary endpoint was rate of decline of lung function, and the composite endpoint could only be derived from endpoints reported in the study. However, mortality (carefully reviewed by a clinical endpoint committee) was a predetermined endpoint of the study. In addition, respiratory failure and severe exacerbation used in this report were collected as adverse events and the cause for discontinuation of the study carefully recorded. Indeed, we believe careful accounting for the differential dropout from clinical trials represents the strength of this analysis because those patients who discontinue the trial prematurely due to worsening disease [20] are characterized by worse patient-related outcomes. Furthermore, patients dropping out from the placebo group have worse patient-related outcomes than those dropping out from the active treatment group. Second, the elements used to define CERO were chosen after the study was completed. However, these were selected because of their clinical validity, careful recording, and value as reflecting the impact of COPD on the patients themselves. Third, the analysis was an on-treatment analysis based on data collected during the treatment period. The intent-to-treat analysis was not feasible because two components of the CERO, severe respiratory failure and severe exacerbation, were not collected after treatment discontinuation. This likely caused an unfavorable bias against tiotropium because more patients discontinued from placebo than from tiotropium; thus, more events in the placebo arm may otherwise have been recorded had the discontinued patients been followed up. Nevertheless, the exposure was adjusted in the calculation of IR and RR in an attempt to address such bias. If the composite endpoint is used as the primary endpoint in a future study, we recommend that all components are followed up after treatment discontinuation in a true intent-to-treat analysis.

This study shows that a composite endpoint incorporating infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. This clinically meaningful approach may help in the design of studies incorporating safety with a feasible sample size; however, further validation of the composite endpoint will be required. In the UPLIFT® trial, the IRs of CERO events were significantly reduced in patients receiving tiotropium.