NLRP3 Inflammasome and Physical Therapy in ICU-Acquired Weakness

NCT07017517 | Recruiting DMC

• 1 other identifier: 001-2025
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 3

Brief Summary

The goal of this clinical trial is to study whether physical therapy can reduce NLRP3 inflammasome activation and muscle atrophy in patients with critical illness myopathy (CIM). It will also explore the role of NLRP3 inflammasome in the pathophysiology of CIM. The main questions this study aims to answer are: Is NLRP3 inflammasome activation associated with muscle atrophy through the upregulation of atrogenes? Does physical therapy attenuate NLRP3 inflammasome activation in skeletal muscle, thereby contributing to the prevention or reduction of muscle atrophy in CIM? Researchers will compare enhanced physical therapy using servo-assisted bed cycling (Motomed Letto®) in critically ill patients at risk of developing CIM during the early phase of ICU stay to conventional physical therapy (standard physiotherapy), to assess whether physical therapy reduces NLRP3 inflammasome activation and muscle degradation. Participants will: Be randomized to receive either conventional physical therapy or enhanced physical therapy (Motomed Letto®) for 7 consecutive days. A control group of patients without CIM will also be included. Undergo assessments of NLRP3 activity, muscle atrophy markers, and transcriptomic profiles from serum and vastus lateralis muscle biopsies. Be clinically evaluated using the SOFA scale and muscle ultrasound for CIM diagnosis. Be followed up for changes in muscle strength and physical functionality. Provide sociodemographic and clinical information to be recorded throughout the study.

Conditions

Critical Illness Myopathy

Keywords

Critical illness myopathy; Physical therapy; NALP3 inflammasome; Muscle atrophy; ICU-acquired weakness

Outcome Measures

Primary Outcomes (11)

• Relative mRNA expression of NLRP3, IL-1β, and IL-18 in muscle tissue (RT-qPCR)

  mRNA levels of NLRP3, IL-1β, and IL-18 will be quantified using RT-qPCR from muscle biopsy samples.

  Baseline and Day 7 (on the final day of intervention)

• Protein expression of phospho-p65S536 and total p65 (Western blot)

  Protein levels of phospho-p65 Serine 536 and total p65 will be assessed by Western blot to evaluate NF-κB pathway activation.

  Baseline and Day 7 (on the final day of intervention)

• Ratio of cleaved/uncleaved caspase-1, IL-1β, and GSDMD-NT (Western blot)

  Cleaved forms of IL-1β, caspase-1, and GSDMD-NT will be quantified by Western blot and normalized to precursor forms.

  Baseline and Day 7 (on the final day of intervention)

• Plasma concentrations of IL-1β and IL-18 (ELISA)

  Plasma levels of IL-1β and IL-18 will be measured using ELISA.

  Baseline and Day 7 (on the final day of intervention)

• Expression of oxidative stress markers and cathepsin B (Western blot)

  Protein carbonylation, nitration, and cathepsin B expression will be analyzed by Western blot.

  Baseline and Day 7 (on the final day of intervention)

• Expression of cathepsin B (RT-qPCR)

  Cathepsin B expression will be analyzed by RT-qPCR.

  Baseline and Day 7 (on the final day of intervention)

• Ultrastructural mitochondrial damage and lysosomal vacuolization (TEM)

  Mitochondrial damage and lysosomal vacuole volume will be assessed by transmission electron microscopy.

  Baseline and Day 7 (on the final day of intervention)

• Muscle fiber diameter (immunofluorescence)

  Fiber diameter in 10 µm cryosections will be measured using anti-laminin immunofluorescence.

  Baseline and Day 7 (on the final day of intervention)

• mRNA expression of atrogenes: MuRF1, Atrogin-1, MUSA1, TRIM62, TRIM32

  Atrogene mRNA levels will be quantified using RT-qPCR from muscle biopsies.

  Baseline and Day 7 (on the final day of intervention)

• Myosin/actin ratio (Western blot)

  Myosin and actin protein levels will be analyzed by Western blot to assess the molecular diagnosis of CIM.

  Baseline and Day 7 (on the final day of intervention)

• Sarcomeric organization (TEM)

  Evaluation of sarcomeric structure in cryosections using transmission electron microscopy.

  Baseline and Day 7 (on the final day of intervention)

Secondary Outcomes (2)

• Differential expression of genes related to atrophy and inflammasome activation (microarray or nanopore-based RNA sequencing )

  Baseline (prior to intervention) and Day 7 of intervention

• Correlation between molecular findings and CIM clinical diagnosis

  From recovery of consciousness (in ICU or follow-up) through 90-day follow-up

Study Arms (2)

Enhanced or Additional Physical Therapy Group

EXPERIMENTAL

Critically ill patients at risk of developing CIM will receive enhanced (additional) physical therapy consisting of standard physiotherapy plus servo-assisted lower-limb cycling using the Motomed Letto® device. Therapy will be delivered twice daily, 60 minutes per session, for 7 consecutive days during the early ICU stay. Muscle biopsies from the vastus lateralis will be collected for histological and molecular analyses.

Device: Motomed Letto® servo-assisted cycling + standard physiotherapy

Conventional Physical Therapy Group

ACTIVE COMPARATOR

Critically ill patients at risk of CIM will receive standard physiotherapy delivered according to institutional ICU rehabilitation protocols. The intervention is delivered at the same frequency and clinical stage as the enhanced therapy group.

Behavioral: Standard physiotherapy

Interventions

Motomed Letto® servo-assisted cycling + standard physiotherapy DEVICE

Servo-assisted cycling using the Motomed Letto® device with a cadence target of 30 revolutions per minute (rpm), performed for 60 minutes twice daily for 7 days. This intervention is administered in addition to standard ICU physiotherapy to critically ill patients at risk of critical illness myopathy (CIM).

Also known as: Motomed Letto®, Additional Physical Therapy, Enhanced Physical Therapy

Enhanced or Additional Physical Therapy Group

Standard physiotherapy BEHAVIORAL

Standard physiotherapy including mobilization and passive/active range-of-motion exercises, delivered during routine ICU care for 7 days.

Also known as: Conventional physical therapy, routine ICU physiotherapy

Conventional Physical Therapy Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Medical diagnosis of sepsis upon ICU admission.
• Receiving invasive mechanical ventilation with a projected requirement ≥7 days.
• SOFA score ≥8 for three consecutive days within the first five days of ICU admission.

You may not qualify if:

• Neurocritical illness.
• Prior malnutrition or cachexia.
• Pre-existing neuromuscular disease.
• Coagulopathy (severe liver disease or continuous dialysis).
• Thrombocytopenia \<20,000 platelets/μL.
• Prior Clinical Frailty Scale ≥4.
• Lower limb amputation or fractures.
• Ongoing chemotherapy.
• Pregnancy.
• BMI \>35.
• Uncontrolled epilepsy.
• Allergy to ultrasound gel.
• Prior prolonged corticosteroid therapy.
• Expected ICU stay \<7 days.
• Imminent death.

Sponsors & Collaborators

• University of Chile: lead
• Clinica Indisa: collaborator
• Hospital de Urgencia y Asistencia Pública: collaborator

Study Sites (3)

Clínica INDISA

Santiago, Metropolitan Region, 7520440, Chile

RECRUITING

Hospital de Urgencia Asistencia Pública (HUAP)

Santiago, Metropolitan Region, 8330075, Chile

RECRUITING

University of Chile

Santiago, Metropolitan Region, 8380453, Chile

RECRUITING

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  PMID: 41703616 DERIVED

MeSH Terms

Conditions

Muscular Atrophy

Condition Hierarchy (Ancestors)

Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Study Officials

• Paola A Llanos, PhD

  University of Chile

  STUDY DIRECTOR

Central Study Contacts

Óscar L Arellano-Pérez, MSc.

CONTACT

+56961479414; oscar.arellano@ug.uchile.cl

Paola A Llanos, PhD

CONTACT

+56997482044; pllanos@odontologia.uchile.cl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, PhD Candidate in Biomedical Sciences, University of Chile

Study Record Dates

• First Submitted: May 26, 2025
• First Posted: June 12, 2025
• Study Start: April 20, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027
• Last Updated: May 6, 2026

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

CL (3)