Respiratory Muscles in End-stage Lung Disease: Pathophysiological Processes & Clinical Consequences

NCT ID: NCT06935825

Last Updated: 2025-04-20

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2025-09-01
• Study Completion Date: 2029-09-01

Brief Summary

Rationale: In patients with chronic lung diseases, the role of respiratory muscle dysfunction has been underestimated. Also, current treatment options, like chronic NIV and lung transplantation (LTx), might also have deleterious effects on the respiratory muscles, and the mechanisms are poorly understood.

Therefore in this exploratory study the objectives are to:

1. Determine in vivo respiratory muscle function and progression of respiratory muscle dys-function in end-stage COPD patients

2. Establish the correlation between changes in the structure and contractility of respiratory myofibers and in vivo respiratory muscle function.

3. Establish the effect of chronic NIV on structure and contractility of respiratory muscle fi-bers

4. Determine whether the structure and contractility of respiratory muscles cells at the time of LTx predicts clinical recovery post-LTx.

Study design: The study will be an exploratory observational cohort study following patients on the LTx waiting list during the waiting period and afterwards until they showed functional recovery of respiratory muscle function.

Study population: Adult COPD patients on the LTx waiting list will be included. Intervention (if applicable): None

Main study parameters/endpoints:

To assess clinical functioning of the respiratory muscles we will assess respiratory electrical activity as a measure of respiratory effort by surface EMG, and thickening fraction of the diaphragm and intercostal muscles and diaphragm excursions by ultrasound and maximal in- and expiratory pressure to assess muscle output; all before and after LTx. We will relate and correct these data for hyperinflation and degree of lung damage by using data from standard care lung function tests and CT scans, and will relate these measurements to prior treatment (NIV settings) and outcome after LTx, by retrieving these data from the EPD.

To assess contractility of respiratory myofibers and in vivo respiratory muscle function, biopsies will be taken during LTx surgery and the biopsies will be analyzed in the lab of Prof. Ottenheijm (AmsterdamUMC) for individual myofiber functioning (strength, calcium sensitivity, myofiber characteristics) and in the lab of Dr. Pouwels for extracellular matrix characteristics.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Overall, risks are believed to be minimal. The clinical measurements are non-invasive and/or regular performed in clinical practice. Also, we decided to do those measurements during regular control visits, limiting the burden for the patients. Taking biopsies from the respiratory muscles during surgery has been extensively performed without any risk; the biobank of the Ottenheijm group contains > 500 samples and never any complication has been observed. Also, in preparation of the present study we performed a pilot study in 12 COPD patients of whom.. biopsies were taken at the UMCG without side effects or complications. The biopsies will be done with the patients being under full anesthesia, so participants will feel no discomfort.

Detailed Description

Considering that a) there is a substantial proportion of patients with severe COPD that develop respiratory muscle dysfunction-induced CHRF; b) respiratory pump failure results in significant morbidity and mortality; and c) the response to current treatment options is highly variable, presumably due to detrimental effects on the respiratory muscle pump, there is a high need for research identifying the pathophysiological mechanisms that underlie respiratory muscle dysfunction in end stage COPD. To meet this need, we will combine in vivo respiratory muscle testing with studies on unique respiratory muscle biopsies to test the hypothesis that respiratory muscle dysfunction is caused by atrophy and reduced contractility of single respiratory myofibers, and that this underlies the development of CHRF. Furthermore, we will test the hypothesis that respiratory muscle dysfunction is exacerbated by NIV and contributes to difficulties in post-LTx recovery. The outcomes will identify targets for intervention and prevention of CHRF.

Conditions

COPD

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

NIV+

Group of patients on nocturnal NIV prior to LTx

No interventions assigned to this group

NIV-/hypercapnic

Group of patients who are chronic hypercapnic but not on NIV prior to LTx

No interventions assigned to this group

normocapnic

Group of normocapnic patients prior to LTx

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Age > 18 years old
• Severe COPD defined as COPD GOLD stage III or IV (FEV1 < 50% of predicted; FEV1/FVC ratio < 70%, no significant reversibility, smoking history of at least 10 pack-years).
• Being on the lung transplant waiting list
• Being able to understand the patient information and provide written informed consent for participation in the study

A potential participant who meets any of the following criteria will be excluded from participation in this study:

• Patients suffering from acute conditions at the time of inclusion or LTx
• Patients using more than 20 mg of morphine, or an equivalent, or more than 20 mg oxazepam, or an equivalent, at the time of inclusion or LTx

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Erasmus Medical Center

OTHER

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: collaborator

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

University Medical Center Groningen

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Amsterdam University Medical Center

Amsterdam, , Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Radboud University Medical Center

Nijmegen, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Countries

Netherlands

Central Contacts

Marieke L Duiverman, MD PhD

Role: CONTACT

m.l.duiverman@umcg.nl

+31503616161

Facility Contacts

Coen Ottenheijm, Prof. Dr.

Role: primary

c.ottenheijm@amsterdamumc.nl

Marieke Duiverman

Role: primary

m.l.duiverman@umcg.nl

Tji Gan, MD PhD

Role: backup

c.t.gan@umcg.nl

Jonne Doorduin

Role: primary

jonne.doorduin@radboudumc.nl

Merel Hellemons, MD PhD

Role: primary

m.hellemons@erasmusmc.nl

Other Identifiers

PaNaMaID: 22059

Identifier Type: -

Identifier Source: org_study_id