Effect of Exercise Order During Pulmonary Rehabilitation on Muscle Strength in Patients With COPD (ISTOR-COPD)

Effect of Intra-Session Training Order of Cardiorespiratory Endurance Work and Muscle Strengthening in COPD Patients

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Other: Pulmonary Rehabilitation - Strength First; Other: Pulmonary Rehabilitation - Endurance First

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 138
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Amandine RAPIN; Phone Number: 0033 03 26 78 42 60; Email: arapin@chu-reims.fr

Study Locations

• France
  • Reims, France, 51092
    • Chu Reims

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Muscle Strengthening Before Endurance Training (MS-ET); Participants assigned to this arm will follow a standardized pulmonary rehabilitation program in which muscle strengthening exercises are systematically performed before cardiorespiratory endurance training within each rehabilitation session. The overall content, frequency, duration, and intensity of the rehabilitation program are identical to those of the comparison arm; only the intra session order of the exercise components differs. Sessions are conducted three times per week over an eight week period under professional supervision.	Other: Pulmonary Rehabilitation - Strength First; All participants receive the same standardized pulmonary rehabilitation program, differing only in the intra-session exercise order. Sessions are supervised, performed 3 times/week for 8 weeks and combine cardiorespiratory endurance and peripheral muscle strengthening. Endurance training consists of 30-45min continuous exercise on a cycle ergometer, treadmill or rowing ergometer, with intensity individually prescribed from baseline exercise testing and adjusted according to tolerance and dyspnea. Strength training lasts 45-60min and targets upper- and lower-limb muscles using dumbbells, elastic bands, body-weight exercises and leg press. Initial training loads are determined from indirect 1-RM estimation. After a familiarization phase, patients perform 6 alternating upper/lower-limb exercises in 3 sets of 8-12 repetitions near maximal effort, with standardized rest periods and movement tempo. Loads are progressively increased according to repetition performance and patient tolerance.
Active Comparator: Endurance Training Before Muscle Strengthening (ET-MS); Participants assigned to this arm will follow a pulmonary rehabilitation program in which muscle strengthening exercises within each rehabilitation session is systematically performed before cardiorespiratory endurance training . The rehabilitation program is identical to that of the standardized arm in terms of content, frequency, duration, and intensity. The only difference between the two arms is the intra session order of endurance and strength exercises. Sessions are conducted three times per week over an eight week period under professional supervision.	Other: Pulmonary Rehabilitation - Endurance First; All participants receive the same standardized pulmonary rehabilitation program, differing only in the intra-session exercise order. Sessions are supervised, performed 3 times/week for 8 weeks and combine cardiorespiratory endurance and peripheral muscle strengthening. Endurance training consists of 30-45min continuous exercise on a cycle ergometer, treadmill or rowing ergometer, with intensity individually prescribed from baseline exercise testing and adjusted according to tolerance and dyspnea. Strength training lasts 45-60min and targets upper- and lower-limb muscles using dumbbells, elastic bands, body-weight exercises and leg press. Initial training loads are determined from indirect 1-RM estimation. After a familiarization phase, patients perform 6 alternating upper/lower-limb exercises in 3 sets of 8-12 repetitions near maximal effort, with standardized rest periods and movement tempo. Loads are progressively increased according to repetition performance and patient tolerance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Five Times Sit to Stand Test (5STS)	Assessment of lower limb muscle strength using a standardized functional test There is no minimum and maximum values in this measure. The higher the score, the worse the result.	End of pulmonary rehabilitation program (8 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Five Times Sit to Stand Test (5STS)	Assessment of lower limb muscle strength using a standardized functional test There is no minimum and maximum values in this measure. The higher the score, the worse the result.	3 months after program completion
Five Times Sit to Stand Test (5STS)	Assessment of lower limb muscle strength using a standardized functional test There is no minimum and maximum values in this measure. The higher the score, the worse the result.	6 months after program completion
Five Times Sit to Stand Test (5STS)	Assessment of lower limb muscle strength using a standardized functional test There is no minimum and maximum values in this measure. The higher the score, the worse the result.	12 months after program completion
6 Minute Walk Test (6MWT)	Assessment of functional exercise capacity using a standardized submaximal walking test There is no minimum and maximum values in this measure. The higher the score, the better the result.	End 3 months after program completion
6 Minute Walk Test (6MWT)	Assessment of functional exercise capacity using a standardized submaximal walking test There is no minimum and maximum values in this measure. The higher the score, the better the result.	End 6 months after program completion
6 Minute Walk Test (6MWT)	Assessment of functional exercise capacity using a standardized submaximal walking test There is no minimum and maximum values in this measure. The higher the score, the better the result.	End 12 months after program completion
Dyspnea (mMRC and Dyspnea 12)	Assessment of dyspnea severity using validated patient reported outcome measures For the modified Medical Resaerch Council (mMRC), the minimum value is 0 and the maximum is 4. The higher the score, the worse the result. For Dyspnea-12 : the minimum value is 0 and the maximal is 36. The higher the score, the worse the results.	End 3 months after program completion
Dyspnea (mMRC and Dyspnea 12)	Assessment of dyspnea severity using validated patient reported outcome measures For the modified Medical Resaerch Council (mMRC), the minimum value is 0 and the maximum is 4. The higher the score, the worse the result. For Dyspnea-12 : the minimum value is 0 and the maximal is 36. The higher the score, the worse the results.	End 6 months after program completion
Dyspnea (mMRC and Dyspnea 12)	Assessment of dyspnea severity using validated patient reported outcome measures For the modified Medical Resaerch Council (mMRC), the minimum value is 0 and the maximum is 4. The higher the score, the worse the result. For Dyspnea-12 : the minimum value is 0 and the maximal is 36. The higher the score, the worse the results.	End 12 months after program completion
Muscle and Inflammatory Biomarkers (Haptoglobin)	Assessment of muscle related and inflammatory biomarkers using blood sample analysis. It will be assessed only at the Reims center Unit of Measure: g/L	Baseline, 1 month, and 2 months
Muscle and Inflammatory Biomarkers (IL-6)	Assessment of muscle related and inflammatory biomarkers using blood sample analysis. It will be assessed only at the Reims center Unit of Measure: pg/mL	Baseline, 1 month, and 2 months
Fatigue score as measured by Numeric Rating Scale (0-10)	Assessment of program tolerance based on fatigue evaluation : Participants rate their fatigue on a 0-10 numeric scale at each assessment point. Unit of Measure: 0-10	Baseline, 1 month, and 2 months
Number of completed sessions out of total planned sessions	The total number of intervention sessions completed by each participant will be recorded and compared to the total number of sessions planned Unit of Measure: Number of sessions	Baseline, 1 month, and 2 months

Collaborators and Investigators

• Sponsor: CHU de Reims

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: May 20, 2026
• First Submitted That Met QC Criteria: June 12, 2026
• First Posted (Actual): June 17, 2026

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pathological Conditions, Signs and Symptoms; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: PN26027*

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No