STIMIT Activator 1 for Diaphragm Dysfunction

Recruiting at 2 trial locations

Overseen By Mary B Tate

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Stimit AG

Must not be taking: Neuromuscular blockers

Disqualifiers: Severe COPD, Metallic implants, BMI >40, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 10 days

40 Participants Needed

Trial Summary

What is the purpose of this trial?

The study is a prospective, multi-center, randomized, controlled study using adaptive design to assess the evidence of safety and performance of the STIMIT Activator 1 System in the treatment of patients who have been mechanically ventilated for up to 48 hours and are predicted to require additional minimum 48 hours of mechanical ventilation or longer (adding up to MV time approximately 96 hours or longer).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on continuous infusion of neuromuscular blocking agents, you may not be eligible to participate.

What data supports the effectiveness of the treatment STIMIT Activator 1 for diaphragm dysfunction?

Research on transcutaneous electrical diaphragmatic stimulation (TEDS), which is similar to the STIMIT Activator 1, suggests that it may help reduce diaphragm dysfunction and improve muscle strength in patients on mechanical ventilation. ^{1 2 3 4 5}

How does the STIMIT Activator 1 treatment for diaphragm dysfunction differ from other treatments?

The STIMIT Activator 1 treatment is unique because it likely involves a novel mechanism or technology not covered by traditional methods like diaphragm plication or diaphragm pacing, which are used to manage symptoms but do not restore diaphragm function. This treatment may offer a new approach to directly improve diaphragm function, unlike existing options that primarily focus on symptom relief. ^{6 7 8 9 10}

Research Team

Laurent Brochard, MD

Principal Investigator

St Michael's Hospital Unity Health Toronto

Eligibility Criteria

This trial is for adults over 21 who have been on a mechanical ventilator for up to 48 hours and are expected to need it for at least another 48 hours. They must be able to give written consent themselves or through a legal representative.

Inclusion Criteria

Informed consent in writing from patient or the legally authorized representative

I am 21 years old or older.

I have been on a breathing machine for less than 2 days and expected to need it for at least 2 more days.

Exclusion Criteria

Any patients with ICP probe

I have severe chronic lung disease.

Patients with metallic device implants or body penetrating metallic devices in the upper body area within 30cm (12inches) from the coils; known anatomy or devices in the neck area (e.g., ECMO cannulas in the neck area, collars or cranial appliances) that would interfere with headset placement or stimulation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive non-invasive stimulation of the phrenic nerve for activation of the diaphragm

Up to 10 days

Daily monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 days or until extubation

Treatment Details

Interventions

• STIMIT Activator 1

Trial Overview The STIMIT Activator 1 System is being tested in this study. It's designed to help patients with diaphragm dysfunction who require prolonged mechanical ventilation. The study compares the safety and performance of this system against standard care in several medical centers.

Participant Groups

Group I: Stimulation Group Experimental Treatment 1 Intervention

The intervention group will receive non-invasive stimulation of the phrenic nerve for activation of the diaphragm.

Group II: Control Group Active Control 1 Intervention

The control group will not received intervention and will be treated with standard of care.

STIMIT Activator 1 is already approved in United States, Canada for the following indications:

Approved in United States as STIMIT Activator 1 for:

• Prevention of diaphragmatic dysfunction/atrophy in mechanically ventilated patients

Approved in Canada as STIMIT Activator 1 for:

• Prevention of diaphragmatic dysfunction/atrophy in mechanically ventilated patients

Who Is Running the Clinical Trial?

Stimit AG

Lead Sponsor

Trials

5

Recruited

70+

Findings from Research

In a study of 126 critically ill patients on mechanical ventilation, 40.5% experienced diaphragmatic dysfunction, which was linked to worse outcomes such as increased risk of pneumonia, extubation failure, longer ventilation duration, and higher mortality rates.

Early amino acid intake within the first 24 hours of ICU admission was identified as a significant modifiable risk factor that may reduce the incidence of diaphragmatic dysfunction by 29% and potentially lower mortality by 49%, highlighting its importance in patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modifiable risk factors for ventilator associated diaphragmatic dysfunction: a multicenter observational study. Pu, H., Doig, GS., Lv, Y., et al.[2023]

In a study of 69 critically ill patients on mechanical ventilation, it was found that 50% did not resume minimal diaphragm activity within the first 24 hours, indicating a common issue of diaphragm inactivity during early mechanical ventilation.

The use of sedative agents, particularly propofol and fentanyl, was identified as a significant factor delaying the resumption of diaphragm electrical activity, regardless of the patient's overall illness severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duration of diaphragmatic inactivity after endotracheal intubation of critically ill patients. Sklar, MC., Madotto, F., Jonkman, A., et al.[2021]

In a study of 112 mechanically ventilated ICU patients, diaphragm thickness and excursion were not correlated with diaphragm function measured by phrenic nerve stimulation at the start of mechanical ventilation, indicating these measures may not be reliable indicators of diaphragm strength.

However, as patients switched to pressure support ventilation, the thickening fraction (TFdi) showed a strong correlation with diaphragm function, and a TFdi of less than 29% was effective in identifying diaphragm dysfunction, which was linked to longer ICU stays and higher mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications. Dubé, BP., Dres, M., Mayaux, J., et al.[2022]

A Phase I clinical trial involving 32 mechanically ventilated children with acute respiratory distress syndrome showed that a computerized decision support tool for ventilator management was accepted over 75% of the time, indicating its feasibility in clinical practice.

Patients using the real-time effort-driven ventilator management had significantly better outcomes, including 6 more ventilator-free days and a shorter duration on mechanical ventilation compared to historical controls, without increasing the rate of reintubation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Time Effort Driven Ventilator Management: A Pilot Study. Hotz, JC., Bornstein, D., Kohler, K., et al.[2022]

In a controlled trial involving 66 ICU patients, transcutaneous electrical stimulation of the diaphragm (TEDS) did not significantly prevent diaphragmatic dysfunction or improve respiratory muscle strength compared to sham stimulation during mechanical ventilation.

Measurements of diaphragm thickening fraction, maximal inspiratory muscle pressure, and peak cough flow showed no meaningful differences between the TEDS and sham groups, indicating that TEDS may not be an effective intervention for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous electrical diaphragmatic stimulation in mechanically ventilated patients: a randomised study. Medrinal, C., Machefert, M., Lamia, B., et al.[2023]

Diaphragm dysfunction, often caused by unilateral paralysis, can significantly impair breathing, reducing ventilatory function by about 25% in adults.

This review examines the effectiveness of diaphragm plication techniques using sutures versus staples, aiming to identify any clinical advantages of one method over the other in treating eventration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stapled Diaphragmatic Plication: Is It Better Than Suture Plication? Hill, TM., Onugha, O.[2020]

Diaphragm pacing (DP) was successfully used in a prospective study involving 27 patients with diaphragm dysfunction, leading to substantial respiratory improvements in 62% of those implanted, indicating its potential as an effective treatment option.

This study highlights that DP can benefit patients with various causes of diaphragm dysfunction, suggesting a broader application beyond its initial indications for spinal cord injury and amyotrophic lateral sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended use of diaphragm pacing in patients with unilateral or bilateral diaphragm dysfunction: a new therapeutic option. Onders, RP., Elmo, M., Kaplan, C., et al.[2022]

In a study involving 30 adult male rats, high tidal volume mechanical ventilation was found to significantly increase TLR4 and TNF-α expression in diaphragm tissues, leading to decreased muscle contraction.

The results suggest that targeting TLR4 signaling could be a potential strategy for preventing and treating diaphragm dysfunction caused by mechanical ventilation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TLR4 signaling is activated in ventilator-induced diaphragm dysfunction in rats. Liu, P., Zhang, H., Hu, K., et al.[2020]

Critically ill patients often experience significant diaphragm weakness, particularly those on mechanical ventilation or suffering from sepsis, which can lead to poor clinical outcomes and difficulties in weaning off ventilator support.

The review highlights that diaphragm dysfunction is linked to shared molecular mechanisms in both mechanical ventilation and sepsis, suggesting potential therapeutic targets for preventing or treating diaphragm weakness in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diaphragm Weakness in the Critically Ill: Basic Mechanisms Reveal Therapeutic Opportunities. Petrof, BJ.[2019]

Diaphragmatic dysfunction, which can arise from various causes like surgery or trauma, is a significant but often overlooked contributor to respiratory issues, typically identified through chest radiography showing diaphragm elevation.

Functional imaging techniques such as fluoroscopy, ultrasonography, or MRI are effective for diagnosing types of diaphragmatic dysfunction, including paralysis, weakness, and eventration, with treatment options like plication and phrenic nerve stimulation tailored to the underlying cause and severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging of the diaphragm: anatomy and function. Nason, LK., Walker, CM., McNeeley, MF., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Modifiable risk factors for ventilator associated diaphragmatic dysfunction: a multicenter observational study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Duration of diaphragmatic inactivity after endotracheal intubation of critically ill patients. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Real-Time Effort Driven Ventilator Management: A Pilot Study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Transcutaneous electrical diaphragmatic stimulation in mechanically ventilated patients: a randomised study. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Stapled Diaphragmatic Plication: Is It Better Than Suture Plication? [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Extended use of diaphragm pacing in patients with unilateral or bilateral diaphragm dysfunction: a new therapeutic option. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

TLR4 signaling is activated in ventilator-induced diaphragm dysfunction in rats. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Diaphragm Weakness in the Critically Ill: Basic Mechanisms Reveal Therapeutic Opportunities. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Imaging of the diaphragm: anatomy and function. [2022]