The Long-Term Oxygen Treatment Trial for Chronic Obstructive Pulmonary Disease: Rationale, Design, and Lessons Learned

Abstract

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).

Keywords: chronic obstructive pulmonary disease; hypoxemia; oxygen; randomized controlled trial; survival.

Figure 1.

Geographic distribution of Long-Term Oxygen Treatment Trial (LOTT) clinics. Forty-seven LOTT clinics in 37 locations screened participants for the LOTT; 42 clinics randomized at least one participant. The map figure may be viewed on the public portion of the LOTT website at www.lottsite.org.

Figure 2.

Long-Term Oxygen Treatment Trial protocol and study conduct timeline. Shaded objects refer to recruitment and follow-up timing. Nonshaded boxes that have a boldface outline show study protocol amendments. Dashed nonshaded boxes show additional protocol changes.

Figure 3.

CONSORT (Consolidated Standards of Reporting Trials [18]) diagrams for the Long-Term Oxygen Treatment Trial: (A) through September 2009 (original protocol) and (B) through end of recruitment in August 2014 (final protocol). 6MW = 6-minute walk; COPD = chronic obstructive pulmonary disease; MMRC = Modified Medical Research Council. Panel B was adapted by permission from Reference .