What is the optimal design of a series of single‑patient (N‑of‑1) crossover trials to evaluate powered exoskeleton‑assisted walking versus usual walking in adults (≥50 years) with stable chronic respiratory disease (e.g., chronic obstructive pulmonary disease, interstitial lung disease, bronchiectasis) who have chronic dyspnea on exertion and limited walking endurance (6‑minute walk distance < 350 m)?

Optimal N-of-1 Trial Design for Powered Exoskeleton-Assisted Walking in Chronic Respiratory Disease

Current clinical practice guidelines do not support powered exoskeleton-assisted walking for adults with chronic respiratory disease, as no evidence exists in pulmonary rehabilitation guidelines or systematic reviews to recommend this intervention. 1, 2, 3

Evidence-Based Standard of Care

Established Pulmonary Rehabilitation Components

The American Thoracic Society (2023) provides strong recommendations (moderate-quality evidence) for comprehensive pulmonary rehabilitation that includes:

• Structured exercise training (endurance and strength training) at high intensity (≥60% maximal work rate) for 20-60 minutes per session, 3-5 times weekly, over 8-12 weeks 1
• Ground-based walking training as the preferred modality when the goal is improving walking endurance, producing greater improvements in endurance shuttle walk time than cycle training 1
• Resistance training at 60-80% of one-repetition maximum to address peripheral muscle weakness, which is directly related to survival and exercise capacity in COPD 1

Why Powered Exoskeletons Are Not Recommended

No guideline or systematic review mentions powered exoskeletons as an intervention for chronic respiratory disease. 1, 2, 3 The 2023 American Thoracic Society guideline, 2013 ATS/ERS statement, and 2019 British Thoracic Society guideline for bronchiectasis collectively reviewed 82+ randomized controlled trials involving 4,674+ participants—none evaluated robotic mobility assistance. 1, 2

Technology recommendations in pulmonary rehabilitation focus exclusively on telerehabilitation (strong recommendation, moderate-quality evidence), which achieves equivalent outcomes to center-based programs for exercise capacity, dyspnea, and quality of life. 1, 2, 3

If Proceeding with N-of-1 Trials Despite Lack of Guideline Support

Critical Design Elements for Crossover Trials

Random assignment to initial treatment sequence (exoskeleton-first vs. usual-walking-first) is mandatory to produce valid results, as only 7 of 13 crossover studies in a methodological review used proper randomization. 4

Time-dependent switching rules must be used rather than disease-state-dependent rules; 10 of 13 valid crossover studies used fixed time periods for treatment phases. 4

Washout periods between treatment phases are essential to eliminate carryover effects, which represent the primary threat to crossover trial validity. 5, 6 For walking interventions:

• Minimum 1-week washout between 8-week treatment periods 1
• Explicitly examine and document the adequacy of washout duration 6
• Results are conditional on acceptance that carryover effects have been eliminated 6

Blinding of the crossover point should be attempted when feasible, though only 3 of 13 crossover studies achieved this. 4

Outcome Measures Aligned with Pulmonary Rehabilitation Standards

Primary outcomes should match those proven responsive in pulmonary rehabilitation trials:

• Exercise capacity: 6-minute walk distance (MCID: 25-35 meters) or incremental shuttle walk test 1, 7
• Dyspnea: Chronic Respiratory Disease Questionnaire dyspnea domain (MCID: 0.5 units) or Transitional Dyspnea Index (MCID: 1 unit) 1
• Health-related quality of life: St. George's Respiratory Questionnaire total score (MCID: 4 points) 1

Secondary outcomes should include:

• Peripheral muscle strength (quadriceps force via hand-held dynamometry or 1-repetition maximum) 1, 7
• Physical activity levels (accelerometry measuring steps/day or minutes of moderate activity) 1, 7
• Adverse events (falls, exacerbations, device-related injuries) 1
• Healthcare utilization (emergency visits, hospitalizations) 1, 7

Treatment Period Duration

Each treatment phase should last 8-12 weeks to align with standard pulmonary rehabilitation program duration, which produces clinically meaningful improvements in all outcome domains. 1 Programs shorter than 8 weeks show inconsistent benefits. 1

Statistical Analysis Requirements

Analyze treatment effects separately by sequence group using intra-individual differences between outcomes in both periods as raw data, applying a standard t-test for independent samples. 5 Crossover trials not analyzed separately by sequence group have limited scientific value. 5

Pre-test for carryover effects is mandatory before pooling data across sequences; if carryover effects are detected, analyze only first-period data as a parallel-group comparison. 5, 6

Calculate effect sizes for all outcomes to determine clinical meaningfulness beyond statistical significance. 7

Critical Pitfalls to Avoid

Do not substitute exoskeleton walking for comprehensive pulmonary rehabilitation that includes exercise training, education, behavioral support, and nutritional assessment—technology should deliver all core components, not replace them. 3

Do not proceed without explicit justification for why standard pulmonary rehabilitation (strong recommendation, moderate-quality evidence) is inadequate for the target population. 1, 2

Do not use disease-state-dependent switching rules (e.g., switching when dyspnea improves), as this invalidates crossover design assumptions. 4, 6

Do not ignore carryover effects; if the pre-test indicates carryover, the entire crossover analysis is invalid and only first-period data can be used. 5, 6

Do not enroll patients with frequent exacerbations (>2 per year), as chest infections are the primary cause of exercise non-adherence and would confound treatment comparisons. 2

Alternative Approach: Standard Pulmonary Rehabilitation First

Before investigating novel devices, ensure patients receive evidence-based pulmonary rehabilitation, which produces:

• Mean improvement of 49 meters in 6-minute walk distance 1
• Dyspnea reduction exceeding minimal important difference (0.72 points on CRQ) 1
• Quality of life improvement of 6.8 points on SGRQ (exceeding MCID of 4 points) 1
• Reduced hospital admissions and mortality risk after exacerbations 1

These benefits are supported by 82 randomized controlled trials in COPD, multiple trials in interstitial lung disease and bronchiectasis, and represent the standard of care. 1