Effects of PBMT-sMF in Mechanically Ventilated Patients

To achieve the proposed objectives it will be performed a multi-center, randomized, triple-blinded (patients, therapists, outcome assessors), placebo-controlled trial, in patients who required mechanical ventilation.

One hundred and twelve patients will be randomly allocated to two treatment groups:

• Active treatment: Patients will receive treatment with the active PBMT-sMF combined with standard of care therapy for a mechanically ventilated patient in the ICU.
• Placebo treatment: Patients will receive treatment with the placebo PBMT-sMF combined with standard of care therapy for a mechanically ventilated patient in the ICU.

The randomization will occur immediately following patients qualification and prior to any additional study activities occurring.

The treatment administration protocol (28-day administration protocol) will comprise: 7-minute treatment administration per day on each consecutive day for four consecutive weeks, for a maximum of 28 consecutive treatments over 28 consecutive days, or until the day of the patient's successful weaning from mechanical ventilation, or until the day of the patient's death, whichever occurs first.

The data will be collected by a blinded assessor.

Due to the nature of the condition being evaluated in this study, the study assessment timeline is patient dependent and will therefore be unique to each patient.

The study will comprise:

• pre-treatment evaluation phase (before starting treatment);
• treatment administration phase (two assessments: after completion of 14 and 28 days of treatment);
• post-treatment evaluation phase (any patient who is not discharged from the hospital or who does not die during the treatment administration and evaluation phase will proceed to the post-treatment administration phase. The post-treatment phase will start on the day immediately following the patient's last day in the treatment administration evaluation phase. The post-treatment phase will end on the day that the patient is discharged from the hospital, or the day that the patient dies prior to discharge from the hospital, whichever occurs firs. Therefore, the duration of the post-treatment administration phase will vary by individual patient. During the post-treatment evaluation period, the following assessments will be recorded once every two weeks, as applicable, with the final post-treatment evaluation visit determined on an individual patient basis, up to 2 years).

P.S.:

• For patients whose successful weaning from mechanical ventilation occurs prior to completion of the 28-day administration protocol, the endpoint assessment visit will occur on or after the day of successful weaning.
• For patients who die before completion of the 28-day administration protocol, the endpoint assessment visit will include outcome measures recorded as close to the date of the patient's death as possible.

The investigators will analyze: 1) Length of stay in the ICU; 2) Diaphragm thickness; 3) Length of stay in the hospital following ICU discharge; 4) Length of time until weaning from mechanical ventilation; 5) Mechanical ventilation parameters: (i) Positive end-expiratory pressure levels (PEEP) and (ii) Fraction of inspired oxygen (FiO2); 6) Arterial blood gas analysis: (i) Arterial partial pressure of oxygen (PO2) and (ii)PO2/FiO2 ratio; 7) Vital signs: blood pressure, heart rate, SpO2, blood glucose, etc.; 8) Blood draw analysis: C-reactive protein (CRP); Tumor necrosis factor-alpha (TNF-α); Vitamin D; erythrocytes; hemoglobin; hematocrit; leucocytes; segmented neutrals; eosinophiles; basophiles; lymphocytes; monocytes; platelet count;8) Survival rate; 9) Local skin reactions; 10) Adverse events and serious adverse events.

The statistical analysis will follow the intention-to-treat principles.

Inclusion criteria

• Legally authorized representative signed informed consent;
• Male or female aged 21 years or older;
• On mechanical ventilation through orotracheal intubation for no more than 72 hours prior to study enrollment or pending mechanical ventilation through orotracheal intubation;
• Predicted to remain on mechanical ventilation for at least 48 hours (≥48 hours) from the time of study enrollment

Exclusion criteria

• Mechanical ventilation initiated longer than 72 hours prior to anticipated enrollment;
• Body Mass Index (BMI) > 40 kg/m²;
• Fever of 100.4°C or higher;
• Situated in the prone position for 24 hours or longer during mechanical ventilation;
• Prognosis of mortality within 72 hours, per the patient's physician;
• Hypersensitivity to light;
• Use of non-invasive ventilation, Continuous Positive Airway Pressure (CPAP) and/or Bilevel Positive Airway Pressure (BiPAP) device for ≥ 50% of the time over the preceding 6 months;
• Tracheostomy;
• Any one or more of the following present on both sides of the neck (bilaterally) at the intended treatment site(s): internal jugular (IJ) venous cannulation; incisions, significant bruising; burn(s); notable skin irritation/rash, or other skin condition that may place the subject at risk from harm from the device treatment;
• Fracture, external or internal hemorrhage, or at risk of hemorrhage following acute trauma or fracture, or known or potential acute occult bleeding (e.g., gastric ulcer, intestine) in the intended treatment areas;
• Metallic device implants or body penetrating metallic devices in the upper body/neck area whose location may interfere with the study device treatment administration. E.g., extracorporeal membrane oxygenation (ECMO) cannula;
• Non-removable electrical/electronic device in the upper body/neck area that may interfere with the study device treatment administration, e.g., -implanted pacemaker or cardiac defibrillator;
• Cardiogenic or septic shock with ongoing severe hemodynamic instability (according to the American College of Chest Physicians definition (that cannot be stabilized within the 48 hours enrollment period);
• Conditions that may limit ultrasonographic assessment of diaphragmatic thickness, e.g., occluding chest drain, pleural effusion, pulmonary consolidation of the lower lobe(s);
• Current cancer of any type;
• Pregnancy;
• Any comorbidity, co-existing condition or illness, or other factor that in the opinion of the study investigator may render the subject unsuitable for participation in the study;
• Admission to the ICU within the last 12 months due to respiratory distress/failure;
• Two or more admissions to the ICU within the prior 12 months for any reason;
• Current participation in another clinical study.