Researchers Explore Benefits of Using Composite End Points in COPD Trials

Composite endpoints for chronic obstructive pulmonary disease (COPD) may be used to predict clinically important deterioration (CID) by including more than just the airflow limitation captured by the forced expiratory volume in 1 second (FEV₁), according to a paper published in Respiratory Research.

Investigators from Germany used the previously reported UPLIFT study and conducted a post hoc analysis in order to test the idea that using a composite endpoint could give a fuller assessment of CID in patients enrolled in COPD clinical trials. The international UPLIFT study included patients with moderate-to-very severe COPD, according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

The authors noted that most investigators measure the impact of interventions by the annual rate of decline of FEV₁ over years. However, manifestation of COPD progression can vary over time and among individuals; some patients may end their involvement in a trial early, “underestimating the true mean rate of decline in the control arm,” the authors said.

CID attempts to measure factors at the individual patient level in order to better capture what might matter more to those with the disease. CID includes trough FEV₁, St. George’s Respiratory Questionnaire (SGRQ) score, and moderate/severe exacerbation. Besides being clinically relevant, these factors are important to a patient’s well-being and predict future outcomes, the researchers said.

Researchers sought to test the validity of CID when only FEV₁ and SGRQ events were confirmed at a later visit by these patients in order to show that CID predicts future outcomes. Their analysis measured time to first CID, defined as time to the first occurrence of at least either a decrease in trough FEV₁ , increase in SGRQ total score, or moderate/severe exacerbation.

To exclude short-term changes in disease, the researchers only included confirmed FEV₁ or SGRQ deteriorations that were present in at least 2 consecutive visits that took place about 5 to 6 months apart.

The analysis included 5652 patients who had both measurements at baseline for FEV₁ and SGRQ; of the total, 2811 received tiotropium and 2841 received placebo.

More than 4 in 5 patients included in the study experienced at least 1 CID during the study period, and exacerbations were more frequent than declines in either FEV1 or SGRQ.

About half of the patients experienced at least 2 of the 3 events qualifying as CID, but fewer patients experienced all 3 events, the investigators found.

A similar proportion of patients in each GOLD group (stage 2, 3, or 4) experienced at least 2 CID events. While a similar proportion of patients classified as GOLD 2 and 3 had a similar rate for experiencing all 3 CID events, only a few patients classified as GOLD 4, or more severe disease, experienced all 3 CID events, the authors said.

FEV₁ decline was sustained between 12 and 48 months after the initial event in a majority of patients, the authors found. SGRQ decline was sustained between 12 and 42 months after the initial event, also in most patients. This was true for the GOLD subgroups, they added.

The authors said that time to first CID event and time to the first occurrence of any of the separate factors was affected by the intervention, with patients receiving tiotropium taking longer to reach the first CID or any number of events compared with those receiving placebo. This held for patients in GOLD 2 and 3 groups but ot as often in the GOLD 4 group.

If patients experienced CID events by month 6, they were more likely to experience a moderate or severe exacerbation, severe exacerbation, or death, and this risk was similar for all GOLD subgroups.

“A composite endpoint of CID is a promising endpoint to assess disease activity in COPD clinical trials and may be a useful outcome that helps clinicians interpret the implications of trial results for individual patient management,” the authors concluded.

Identifying patients based on time to CID may make it possible to predict which ones may need earlier treatment, the authors wrote. In addition, using a composite endpoint may allow for reduced number of patients in clinical trials, as well as reduced length of such trials, they said.

Reference

Rabe, K.F., Halpin, D.M.G., Han, M.K. et al. Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial. Respir Res. Published online July 9, 2020. doi:10.1186/s12931-020-01431-y