Pulmonology · Medical Literature
Feasibility assessment of double-blind, crossover, randomized controlled trial protocol comparing two oxygen-supplemented pulmonary rehabilitation for patients with chronic obstructive pulmonary disease: A pilot study.
Abstract
Pulmonary rehabilitation (PR) for patients with chronic obstructive pulmonary disease (COPD) improves exercise tolerance and COPD assessment test score (CAT). Oxygen supplementation during PR facilitates exercise physiological benefits. This study aimed to assess the feasibility of a trial comparing two oxygen supplementation methods, with the hypothesis that both would be effective and produce distinct outcomes. This double-blind, crossover, randomized controlled trial compared two PR programs-Program A (including PR under FiO₂ 0.3) and Program B (including PR under FiO₂ 0.5)-using high-flow nasal cannula oxygen therapy in patients with COPD and exertional dyspnea (n = 6). Data on the 6-minute walk distance (6MWD), CAT, muscle strength, body composition analysis, respiratory function, and joint range of motion were collected. Participants underwent one month of regular PR followed by two months of oxygen-supplemented PR, with data collected again after this period. Statistical significance was set at 0.05 with a power of 0.8, and the required sample size was calculated accordingly. The required sample size could not be calculated based on the 6MWD. The improvement in CAT by Program A was greater than that by Program B. The improvements in muscle parameters by Program B were greater than those by Program A. The standardized effect size and the corresponding required sample sizes for the CAT, quadriceps muscle power, lower leg circumference, trunk muscle mass, and leg muscle mass were 0.32/81, 0.66/8, 0.17/114, 0.27/88, and 0.24/56, respectively. Given the small number of participants, the 6MWD and CAT were not appropriate primary endpoints for comparing the effectiveness of the two oxygen supplementations during PR in patients with COPD. However, the quadriceps muscle power was identified as the most suitable primary endpoint among all the investigated parameters.
Clinical relevance
Is a double-blind, crossover randomized controlled trial protocol comparing pulmonary rehabilitation delivered under FiO₂ 0.3 versus FiO₂ 0.5 via high-flow nasal cannula feasible in patients with COPD and exertional dyspnea, and can an adequate sample size be determined from pilot data? __SNAPSHOT__ {"studyDesign":"Pilot feasibility assessment of a double-blind, crossover randomized controlled trial (RCT) protocol","setting":"Not reported in the abstract; based on overlapping authorship with a companion study (PMID 40669279), likely a Japanese hospital-based rehabilitation setting (International University of Health and Welfare, Tochigi, Japan)","sampleSize":"n = 6 (single pilot cohort; crossover design — Program A [FiO₂ 0.3] and Program B [FiO₂ 0.5] each completed by all participants)","population":"Adults with COPD and exertional dyspnea; specific GOLD stage, FEV₁% predicted, baseline 6MWD, and demographic characteristics not reported in the abstract","intervention":"Program B: pulmonary rehabilitation (PR) delivered under FiO₂ 0.5 via high-flow nasal cannula (HFNC) oxygen therapy, following one month of standard PR run-in","comparator":"Program A: pulmonary rehabilitation delivered under FiO₂ 0.3 via HFNC oxygen therapy (active comparator; no placebo or room-air control arm)","primaryOutcome":"Feasibility of the RCT protocol, specifically whether an adequate required sample size could be calculated; secondary measures collected included 6-minute walk distance (6MWD), COPD Assessment Test (CAT) score, muscle strength, body composition analysis, respiratory function, and joint range of motion","followUp":"Three months total per participant: one month of standard PR run-in followed by two months of oxygen-supplemented PR; crossover washout duration not reported","fundingSource":"Not reported"}
Key findings
The central feasibility finding — the primary outcome of this pilot — was that the required sample size for a future definitive RCT could NOT be calculated based on 6MWD data. This represents a negative feasibility result for the 6MWD as the primary efficacy endpoint of a future full-scale trial. No between-group effect sizes, confidence intervals, p-values, or descriptive statistics for 6MWD or CAT are reported in the available abstract. Outcomes for muscle strength, body composition, respiratory function, and joint range of motion were collected but results are not reported in the abstract. Whether sample size calculation succeeded for any secondary outcome (e.g., CAT score) is not stated in the available abstract. No adverse events are reported in the abstract. All statistical parameters (α = 0.05, power = 0.80) were pre-specified for sample size planning purposes.
Practice implications
This pilot study did not establish that a full-scale double-blind crossover RCT comparing FiO₂ 0.3 versus FiO₂ 0.5 HFNC-supplemented pulmonary rehabilitation is feasible using 6MWD as the primary endpoint — the study's own stated conclusion is that the required sample size could not be calculated from these data. This failure of sample size determination may reflect: (1) the small pilot sample (n = 6), which provides unstable variance estimates; (2) high within-participant variability in 6MWD response to PR across a crossover design; or (3) insufficient between-condition effect size to differentiate FiO₂ 0.3 from FiO₂ 0.5. The hypothesis that both oxygen concentrations are effective but produce distinct outcomes remains unconfirmed. Patients studied had COPD with exertional dyspnea; those with more severe airflow obstruction, those requiring long-term oxygen therapy at rest, or those with significant comorbidities are unlikely to be adequately represented given the small sample. This study does not provide actionable guidance for changing current practice in oxygen supplementation during PR. Only an abstract was available for review; full data, including participant characteristics, raw outcome values, adverse events, and complete feasibility metrics, could not be evaluated. __LIMITATIONS__ Extremely small sample size (n = 6), which is insufficient to generate stable variance estimates for sample size calculation and precludes any meaningful inference about between-condition efficacy differences.,The primary feasibility endpoint (calculability of sample size based on 6MWD) was not met, meaning the protocol as designed cannot proceed directly to a full-scale RCT without modification.,Crossover design introduces risk of carryover effects; duration and adequacy of washout between PR programs are not reported in the abstract.,Both arms received active oxygen supplementation (FiO₂ 0.3 vs. 0.5); absence of a room-air or sham control arm limits understanding of absolute benefit of either oxygen level.,Whether 'double-blind' was achievable in practice with high-flow nasal cannula delivering different FiO₂ levels — and how blinding was verified — is not described in the abstract.,Selection of 6MWD as the primary endpoint for sample size planning may be suboptimal given its known high variability in PR studies; alternative endpoints (e.g., CAT score, endurance time) may have been more statistically tractable but are not assessed for feasibility in the abstract.,Absence of reported descriptive statistics, effect sizes, or adverse event data in the abstract prevents independent critical appraisal of results.,Generalizability is severely limited by single-center (presumed), small-sample, short-term design with no long-term follow-up beyond the three-month intervention window.,Funding source is not disclosed, precluding assessment of sponsorship-related bias.,Only the abstract was available for this review; full-text data including participant demographics, GOLD staging, safety data, and detailed results may modify interpretation. __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ This pilot study found that a required sample size for a full-scale double-blind crossover RCT comparing FiO₂ 0.3 versus FiO₂ 0.5 HFNC-supplemented pulmonary rehabilitation in COPD could not be determined from 6MWD data in 6 participants, representing a negative feasibility outcome for the proposed trial design. The study neither confirms nor refutes the clinical hypothesis that higher FiO₂ during PR produces distinct outcomes, and provides no basis for changing current practice. Future work should focus on identifying a more sensitive primary endpoint, expanding pilot sample size, and confirming blinding fidelity before proceeding to a full-scale efficacy trial.