Chronic Obstructive Pulmonary Disease (COPD) is a chronic multisystem disease frequently associated with peripheral muscle dysfunction, which is strongly linked to prognosis and survival. Pulmonary rehabilitation is a cornerstone of COPD management and includes both cardiorespiratory endurance training and muscle strengthening exercises. Although these components are routinely combined within rehabilitation programs, the optimal order in which they should be performed during the same training session remains unclear.

In healthy individuals, performing endurance and strength exercises in different sequences within a single session may influence muscular adaptations, a phenomenon referred to as the intra session interference effect. This effect has never been studied in patients with COPD undergoing pulmonary rehabilitation. Given the high prevalence and clinical importance of muscle weakness in COPD, optimizing exercise prescription may improve functional outcomes and long term benefits.

This multicenter randomized controlled trial aims to compare two pulmonary rehabilitation strategies that differ only in the order of exercise administration. Participants with moderate to severe COPD will be randomly assigned to perform either muscle strengthening before endurance training or endurance training before muscle strengthening during each rehabilitation session.

The primary objective is to evaluate the impact of exercise order on lower limb muscle strength, assessed by the Five Times Sit to Stand test at the end of the rehabilitation program. Secondary objectives include assessment of exercise capacity, dyspnea, muscle and inflammatory biomarkers, tolerance, and adherence to the rehabilitation program, as well as follow up evaluations up to 12 months after completion.

The results of this study are expected to provide evidence to optimize pulmonary rehabilitation programs for patients with COPD and to inform clinical practice regarding exercise sequencing.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory respiratory condition with systemic consequences, particularly affecting skeletal muscle structure and function. Peripheral muscle dysfunction is common in patients with COPD and is independently associated with reduced exercise capacity, impaired quality of life, increased morbidity, and mortality. Pulmonary rehabilitation is a central component of COPD management and is strongly recommended for symptomatic patients. Comprehensive pulmonary rehabilitation programs typically combine cardiorespiratory endurance training and peripheral muscle strengthening, along with ventilatory physiotherapy and therapeutic education.

While both endurance training and muscle strengthening are known to be effective, the optimal modalities for combining these interventions remain incompletely defined. In particular, the order in which endurance and strength exercises are performed during the same training session may influence physiological adaptations. In healthy populations, concurrent training studies have demonstrated an intra session interference effect, whereby endurance exercise performed prior to strength training may attenuate strength gains. Meta analyses conducted in healthy and athletic populations suggest that performing muscle strengthening before endurance training results in greater improvements in muscle strength. However, this phenomenon has never been investigated in patients with COPD, despite the high prevalence and clinical significance of muscle impairment in this population.

The ISTOR COPD study is designed to evaluate whether the intra session order of muscle strengthening and cardiorespiratory endurance training influences functional outcomes in patients undergoing pulmonary rehabilitation for COPD. This is a multicenter, randomized, controlled, superiority trial with two parallel intervention groups.

Study Design and Setting The study will be conducted in five pulmonary rehabilitation centers in France, including university hospitals and specialized rehabilitation facilities. Eligible patients admitted for pulmonary rehabilitation will be screened consecutively. Following the provision of oral and written information and the signing of informed consent, participants will be randomized in a 1:1 ratio using a centralized, computer generated allocation sequence stratified by center.

Interventions All participants will receive a standardized pulmonary rehabilitation program delivered according to international and national recommendations. The program will include three supervised rehabilitation sessions per week over an eight week period (total of 24 sessions). Each session will incorporate both peripheral muscle strengthening and cardiorespiratory endurance training, with the same total duration, intensity targets, and weekly frequency in both study arms.

The only difference between groups will be the order in which the two components are performed within each session:

• In the first group, muscle strengthening is performed before cardiorespiratory endurance training.
• In the second group, cardiorespiratory endurance training is performed before muscle strengthening.

A standardized rest period (≤ 1 hour) may be allowed between the two components when required by local organization.

Muscle Strengthening Muscle strengthening sessions will last 45 to 60 minutes, with a uniform duration across all participating centers, and will target both lower- and upper-limb muscle groups, with a particular focus on lower-limb muscles involved in functional mobility. The primary objective of muscle strengthening is to achieve gains in muscle strength. Training intensity will therefore be prescribed according to a strength-oriented protocol, standardized across centers and parameterized based on an indirect estimation of the one-repetition maximum (1-RM). Exercises will be performed using free weights (dumbbells), elastic resistance bands, body-weight exercises, and a leg press device. For each targeted muscle group, exercises will be conducted using 8 to 12 repetitions per set, consistent with strength-training recommendations, with systematic progression of training load to maintain an effective stimulus throughout the rehabilitation program.

Cardiorespiratory Endurance Training Endurance training sessions will last 30 to 45 minutes and will be conducted on a cycle ergometer, treadmill, or rowing ergometer, depending on patient capabilities and center equipment. Training intensity will be prescribed based on pre rehabilitation cardiopulmonary exercise testing or dyspnea thresholds. Sessions will include a warm up phase, a continuous endurance training phase at the prescribed intensity, and a recovery phase. Oxygen supplementation will be provided during exercise when clinically indicated.

Outcome Assessment Outcome assessments will be conducted by trained assessors who are independent of the rehabilitation team and blinded to group allocation. The primary outcome is lower limb muscle strength, assessed using the Five Times Sit to Stand test at the end of the rehabilitation program. This functional test is widely validated in COPD, easily applicable in routine clinical settings, and strongly associated with clinical outcomes including survival.

Secondary outcomes include repeated measurements of muscle strength, functional exercise capacity assessed by the 6 Minute Walk Test, dyspnea assessed using the modified Medical Research Council scale and the Dyspnea 12 questionnaire, and tolerance to the rehabilitation program evaluated through session adherence and fatigue scores. Exploratory biological outcomes include muscle and inflammatory biomarkers (haptoglobin and interleukin 6) measured in a subset of patients.

Participants will be followed for up to 12 months after completion of the rehabilitation program, with evaluations conducted at 3, 6, and 12 months to assess the persistence of functional benefits.

Statistical Considerations The trial is powered to detect a clinically meaningful between group difference in the Five Times Sit to Stand test at the end of rehabilitation. Analyses will be conducted primarily according to the intention to treat principle. Between group comparisons will be performed using appropriate parametric or non parametric methods, with adjustment for predefined covariates including center, age, sex, and COPD severity using multivariable regression models.

Expected Contribution This study is the first randomized controlled trial to specifically investigate the intra session exercise order effect in pulmonary rehabilitation for COPD. By isolating the impact of exercise sequencing within otherwise identical rehabilitation programs, the trial aims to provide practical evidence to optimize rehabilitation prescription. The findings may directly inform clinical practice guidelines and have broader implications for exercise based rehabilitation in other chronic respiratory, cardiovascular, and neurological diseases.

Inclusion Criteria:

• Age ≥ 18 years
• COPD GOLD stages 2 to 4
• Admitted for pulmonary rehabilitation in a participating center
• Ability to read and speak French
• Written informed consent
• Affiliation with a social security system

Exclusion Criteria:

• Legal protection (guardianship or trusteeship)
• Pregnancy beyond the second trimester
• Musculoskeletal disorders affecting lower limb strength or walking performance
• Vascular disease limiting walking distance
• Cardiac contraindication to pulmonary rehabilitation