SepsisDISCUSSNCT02789995
Dysfunctions of Human Muscle Stem Cells in Sepsis
A study testing Human biological samples in people with Sepsis, run by Institut Pasteur at 7 sites in France.
Trial summary
Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Sepsis
- What is being tested?
- Human biological samples
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 93 participants
- Where
- 7 sitesFrance
- Study dates
- 23 Jun 2016to 28 Jun 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Affiliated or beneficiary of a social security system
- Informed consent to research :
- Consent from patient, Or consent from patient and close relative, Or non-objection from family for biological sample donation for research.
- Population 1 (sepsis) : Patients hospitalized in Intensive Care Unit, with intra-abdominal sepsis requiring emergency surgery.
- Population 2 (inflammatory condition with or without sepsis) : Brain dead patients scheduled for multi organ retrieval (2a) ; Patients with refractory cariogenic shock and requiring surgery for assistance with (2b).
- Population 3 (control) : Patients scheduled for intra-abdominal surgery.
Who cannot join
- Patient with preexisting neuromuscular disease
- Under 18 year-old
- Pregnancy..
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
France7 sites
Hopital Henri Mondor, Service de Réanimation chirurgicale polyvalente
Créteil, 94010
Hôpital Pitié Salpétrière, Salle de surveillance post-interventionnelle, Accueil des Polytraumatisés
Paris, 75013
Hôpital Pitié Salpêtrière, Anesthésie et Réanimation, Institut de Cardiologie
Paris, 75013
Hôpital Pitié Salpêtrière, Service de Chirurgie Générale, Viscérale et Endocrinienne
Paris, 75013
Hôpital Pitié Salpêtrière, Service de Chirurgie Hépatobiliaire et de Transplantation Hépatique
Paris, 75013
Hôpital Pitié Salpêtrière, Service de réanimation chirurgicale polyvalente
Paris, 75013
Hôpital Saint-Antoine, Département d'Anesthésie-réanimation
Paris
About this study
Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional. Several mechanisms have been incriminated in the pathophysiology of ICU-AW, but muscle regeneration has not been well investigated in this context, even though its involvement is suggested by the protracted functional consequences of ICU-AW. Recent data suggest that muscle regeneration could be impaired after sepsis, and that Mesenchymal Stem Cells (MSCs) treatment could improve the post-injury muscle recovery.
Read the detailed description
Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is clinically characterized by bilateral and symmetrical limb weakness and is related to a myopathy and/or axonal polyneuropathy. ICU-AW affects between 25% to 60% mechanically ventilated patients more than 7 days and is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional disability. Most patients who develop an ICU-AW have been admitted for a sepsis episode and the main risk factors of ICU-AW include the severity of critical illness, immobilization, hyperglycemia and the use of some medications including steroids and neuromuscular agents, although this is somewhat controversial.
The pathophysiology of critical illness myopathy is thought to involve the following mechanisms: 1) impairment of muscular membrane excitability, secondary to an dysregulation of sodium channel gating, 2) mitochondrial dysfunction leading to bioenergetic failure and oxidative stress and 3) proteolysis, mainly related an activation of the ubiquitin-proteasome pathway. These mechanisms can be triggered by various factors, notably systemic inflammatory mediators, endocrine dysfunction, immobilization, some drugs and electrolyte disturbances. The protracted functional consequences of ICU-AW indicate that muscle regeneration is also impaired. Surprisingly, muscle regeneration, which essentially depends on the muscle stem cells (also called satellite cells), has not been well investigated in the context of critical illness. The satellite cells (SC), that are located at the periphery of the muscle fiber, are activated in response to any muscle injury and then proliferate and differentiate to repair or replace the damaged fibers, but also self-renew to replenish the muscle stem cells reservoir.
It was recently demonstrated in a murine model of polymicrobial peritonitis that SC activation, proliferation and expression of myogenic markers were impaired after sepsis, leading to an impaired muscle regeneration, but that post-sepsis intramuscular administration of exogenous Mesenchymal Stem Cells (MSCs) could reverse this SC dysfunction. MSC treatment significantly improved the post-injury muscle recovery with decreasing necrosis and fibrosis but also increased the force of isolated single fibers.
The objectives of this translational research are to identify the mechanisms of Human SC dysfunction in patients with severe sepsis, to describe in vitro the effects of MSCs on this SC dysfunction, and to study hematopoietic cells and their damage in the blood and muscle consecutively to a sepsis, and their interaction with muscle stem cells.
- Conditions
- Sepsis
- Being tested
- Human biological samples
- Keywords
- Intensive Care Unit - Acquired Weakness (ICU-AW)
- Medical subject headings
- Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Human biological samplesProcedure or surgery
Blood sample - Muscle biopsy - Bone marrow sample (mesenchymal stem cells)
| Study group | Role | What they receive |
|---|---|---|
| Patients with and without sepsis | Experimental | Patients with sepsis, Patients with inflammatory disease without sepsis, Patients without inflammatory disease without sepsis.
Human biological samples collected for research :
* Blood sample
* Muscle biopsy
* Bone marrow sample (mesenchymal stem cells) Receives: Procedure: Human biological samples |
What is being measured
The primary outcome is the main question the study is designed to answer.
Muscle regenerative capacities
The muscle regenerative capacity after sepsis would be assessed by the presence of anisocytosis, the proportion of small atrophic fibers, the proportion of endomysial fibrosis of the total muscle section area and the presence of calcified necrotic myofibers.
Measured: 3 years
Secondary outcomes (2)
Satellite cell dysfunction after sepsis
- Number of satellite cells (SC)
- Proportion of cells actively cycling
- Capacity of SC to differentiate into myofibers
Measured: 3 years
Regenerative capacities of Human satellite cells in presence of mesenchymal stem cells
- Number of satellite cells (SC)
- Proportion of cells actively cycling
- Capacity of SC to differentiate into myofibers
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jun 2016 (estimated)
- Study start23 Jun 2016
- Primary completion28 Jun 2018
- Study completion28 Jun 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Institut PasteurThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 93 participants (actual)
Sponsor and investigators
- Lead sponsor
- Institut Pasteur
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Fabrice Chrétien, Study director, Institut Pasteur
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02789995
- Sponsor's protocol ID
- 2015-015
- Other IDs
- ID-RCB number : 2015-A01022-47
- Acronym
- DISCUSS
- Status last verified
- Oct 2019
- First submitted
- 18 May 2016
- Last updated
- 1 Nov 2019
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Rocheteau P, Chatre L, Briand D, Mebarki M, Jouvion G, Bardon J, Crochemore C, Serrani P, Lecci PP, Latil M, Matot B, Carlier PG, Latronico N, Huchet C, Lafoux A, Sharshar T, Ricchetti M, Chretien F. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun. 2015 Dec 15;6:10145. doi: 10.1038/ncomms10145.
PubMed 26666572Duceau B, Blatzer M, Bardon J, Chaze T, Giai Gianetto Q, Castelli F, Fenaille F, Duarte L, Lescot T, Tresallet C, Riou B, Matondo M, Langeron O, Rocheteau P, Chretien F, Bougle A. Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle. Sci Rep. 2022 Nov 5;12(1):18776. doi: 10.1038/s41598-022-23544-8.
PubMed 36335235
Study at a glance
From the registry record, last updated by the sponsor on 1 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dysfunctions of Human Muscle Stem Cells in Sepsis
- ClinicalTrials.gov ID
- NCT02789995
- Acronym / sponsor ID
- DISCUSS / 2015-015
- Conditions
- Sepsis
- Keywords
- Intensive Care Unit - Acquired Weakness (ICU-AW)
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 93 participants (actual)
- Lead sponsor
- Institut PasteurIndustry (pharma, biotech, devices)
- Study start
- 23 Jun 2016 (actual)
- Primary completion
- 28 Jun 2018 (actual)
- Study completion
- 28 Jun 2018 (actual)
- First posted
- 3 Jun 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional. Several mechanisms have been incriminated in the pathophysiology of ICU-AW, but muscle regeneration has not been well investigated in this context, even though its involvement is suggested by the protracted functional consequences of ICU-AW. Recent data suggest that muscle regeneration could be impaired after sepsis, and that Mesenchymal Stem Cells (MSCs) treatment could improve the post-injury muscle recovery.
Detailed description
Severe critical illness is often complicated by Intensive Care Unit - Acquired Weakness (ICU-AW), which is clinically characterized by bilateral and symmetrical limb weakness and is related to a myopathy and/or axonal polyneuropathy. ICU-AW affects between 25% to 60% mechanically ventilated patients more than 7 days and is associated with increased in and post-ICU mortality, with delayed weaning from mechanical ventilation and with long-term functional disability. Most patients who develop an ICU-AW have been admitted for a sepsis episode and the main risk factors of ICU-AW include the severity of critical illness, immobilization, hyperglycemia and the use of some medications including steroids and neuromuscular agents, although this is somewhat controversial.
The pathophysiology of critical illness myopathy is thought to involve the following mechanisms: 1) impairment of muscular membrane excitability, secondary to an dysregulation of sodium channel gating, 2) mitochondrial dysfunction leading to bioenergetic failure and oxidative stress and 3) proteolysis, mainly related an activation of the ubiquitin-proteasome pathway. These mechanisms can be triggered by various factors, notably systemic inflammatory mediators, endocrine dysfunction, immobilization, some drugs and electrolyte disturbances. The protracted functional consequences of ICU-AW indicate that muscle regeneration is also impaired. Surprisingly, muscle regeneration, which essentially depends on the muscle stem cells (also called satellite cells), has not been well investigated in the context of critical illness. The satellite cells (SC), that are located at the periphery of the muscle fiber, are activated in response to any muscle injury and then proliferate and differentiate to repair or replace the damaged fibers, but also self-renew to replenish the muscle stem cells reservoir.
It was recently demonstrated in a murine model of polymicrobial peritonitis that SC activation, proliferation and expression of myogenic markers were impaired after sepsis, leading to an impaired muscle regeneration, but that post-sepsis intramuscular administration of exogenous Mesenchymal Stem Cells (MSCs) could reverse this SC dysfunction. MSC treatment significantly improved the post-injury muscle recovery with decreasing necrosis and fibrosis but also increased the force of isolated single fibers.
The objectives of this translational research are to identify the mechanisms of Human SC dysfunction in patients with severe sepsis, to describe in vitro the effects of MSCs on this SC dysfunction, and to study hematopoietic cells and their damage in the blood and muscle consecutively to a sepsis, and their interaction with muscle stem cells.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with and without sepsis | Experimental | Procedure: Human biological samplesPatients with sepsis, Patients with inflammatory disease without sepsis, Patients without inflammatory disease without sepsis. Human biological samples collected for research : * Blood sample * Muscle biopsy * Bone marrow sample (mesenchymal stem cells) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Affiliated or beneficiary of a social security system
- Informed consent to research :
- Consent from patient, Or consent from patient and close relative, Or non-objection from family for biological sample donation for research.
- Population 1 (sepsis) : Patients hospitalized in Intensive Care Unit, with intra-abdominal sepsis requiring emergency surgery.
- Population 2 (inflammatory condition with or without sepsis) : Brain dead patients scheduled for multi organ retrieval (2a) ; Patients with refractory cariogenic shock and requiring surgery for assistance with (2b).
Key exclusion criteria (3 listed)
- Patient with preexisting neuromuscular disease
- Under 18 year-old
- Pregnancy..
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Human biological samplesBlood sample - Muscle biopsy - Bone marrow sample (mesenchymal stem cells) | Procedure or surgery | Patients with and without sepsis |
Primary outcome
Muscle regenerative capacities
Time frame: 3 years
The muscle regenerative capacity after sepsis would be assessed by the presence of anisocytosis, the proportion of small atrophic fibers, the proportion of endomysial fibrosis of the total muscle section area and the presence of calcified necrotic myofibers.
2 secondary outcomes
Satellite cell dysfunction after sepsis
Time frame: 3 years
Regenerative capacities of Human satellite cells in presence of mesenchymal stem cells
Time frame: 3 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Nov 2019.
- Background: PubMed 26666572Rocheteau P, Chatre L, Briand D, Mebarki M, Jouvion G, Bardon J, Crochemore C, Serrani P, Lecci PP, Latil M, Matot B, Carlier PG, Latronico N, Huchet C, Lafoux A, Sharshar T, Ricchetti M, Chretien F. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun. 2015 Dec 15;6:10145. doi: 10.1038/ncomms10145.
- Derived from this study: PubMed 36335235Duceau B, Blatzer M, Bardon J, Chaze T, Giai Gianetto Q, Castelli F, Fenaille F, Duarte L, Lescot T, Tresallet C, Riou B, Matondo M, Langeron O, Rocheteau P, Chretien F, Bougle A. Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle. Sci Rep. 2022 Nov 5;12(1):18776. doi: 10.1038/s41598-022-23544-8.
- Individual participant dataSharing planned: No
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Not yet recruitingPhase 2/3
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Double Plasma Separation and Adsorption in Acute-on-Chronic Liver Failure (DPMAS-ACLF Trial)
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Active, not recruitingPhase 4
Thymosin Alpha 1 and IgM Levels in Sepsis
Sepsis, Septic Shock
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fabrice Chrétien study director
Institut Pasteur
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Human biological samples in people with Sepsis, run by Institut Pasteur at 7 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Muscle regenerative capacities (time frame: 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02789995, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2019.