<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03770442</url>
  </required_header>
  <id_info>
    <org_study_id>UoL001367</org_study_id>
    <nct_id>NCT03770442</nct_id>
  </id_info>
  <brief_title>Muscle Wasting in the Critically Ill</brief_title>
  <official_title>Effect of Early Rehabilitation Using an Active/Passive Cycling Device on Muscle Wasting in the Critically Ill: A Randomised Controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Liverpool</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Liverpool</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Muscle wasting is a common consequence of critical illness, and has a profound impact upon&#xD;
      the rehabilitation of those who survive admission to critical to care. The investigators&#xD;
      intend to assess if the application of 10 sessions over two weeks of passive cycling with&#xD;
      electrical stimulation to the lower limbs and abdomen can prevent muscle loss, or at least&#xD;
      cause less muscle loss, compared to patients who receive standard daily sessions of&#xD;
      physiotherapy. This will be done by comparing the changes in muscle size on ultrasound&#xD;
      between the two groups, comparing functional measures at a 3 month follow up, and by&#xD;
      performing translational research using tissue samples taken during the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients are mechanically ventilated and sedated with a diagnosis of sepsis (from any source)&#xD;
      will be eligible for this study. Provided they meet the inclusion criteria, they will be&#xD;
      randomised within 48 hours of admission, to either ten 30 minute sessions of passive cycling&#xD;
      with functional electrical stimulation (FES) to the thighs, hamstrings, calves and abdomen&#xD;
      over a 14 day period, or to a control group of routine physiotherapy. The trial group will&#xD;
      also receive this physiotherapy.&#xD;
&#xD;
      On admission to the study, all patients will receive on day 1:&#xD;
&#xD;
      Ultrasound measurements of:&#xD;
&#xD;
      Rectus femoris cross-sectional area Thickness of rectus femoris and vastus intermedius&#xD;
      Thickness, pennation angle and derived fascicle length of vastus lateralis and medial head of&#xD;
      gastrocnemius Thickness of rectus abdominis. Thickness of diaphragm&#xD;
&#xD;
      A blood sample taken from an arterial line A urine sample taken from a urinary catheter A&#xD;
      muscle biopsy taken from the right vastus lateralis&#xD;
&#xD;
      They will then receive ten 30 minute sessions of passive cycling with functional electrical&#xD;
      stimulation over 14 days, or a control group will receive routine physiotherapy during this&#xD;
      period.&#xD;
&#xD;
      Repeat ultrasounds will be taken at days 3, 5, 7, 10 and 14. Repeat blood and urine sampling&#xD;
      at days 5, 10 and 14. Repeat muscle biopsy at day 14.&#xD;
&#xD;
      All cycling, ultrasounds and tissue sampling will end on day 14 regardless of the ventilator&#xD;
      status of the patient.&#xD;
&#xD;
      In patients who survive to be discharged from critical care, they will be followed up at 3&#xD;
      months for:&#xD;
&#xD;
      Repeat ultrasound scan of all muscles listed Six minute walk test Hand grip and lower limb&#xD;
      dynamometry, Balance testing (by standing upright on a pressure plate for 20 seconds)&#xD;
      Psychological assessment using the 36 item Short Form (SF-36) questionnaire&#xD;
&#xD;
      Tissue sampling will be stored in the University of Liverpool for analysis of biomarkers of&#xD;
      muscle damage and loss between the two groups.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 14, 2019</start_date>
  <completion_date type="Actual">November 1, 2020</completion_date>
  <primary_completion_date type="Actual">November 1, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Ultrasound images will be labelled by their participant number, and not by intervention. Therefore, when image analysis takes place, the investigators will not know whether the images come from somebody who received cycling sessions or the control group.&#xD;
Tissue samples will be treated in the same way.&#xD;
In follow up sessions, participants will be asked not to reveal if they can remember whether they cycled or not.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Ultrasound assessment of rectus femoris - Change in cross sectional area (cm2)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement of cross-sectional area of rectus femoris (cm2)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of rectus femoris - Change in muscle layer thickness (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement on muscle layer thickness of rectus femoris (cm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of anterior thigh musculature - Change in muscle layer thickness (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement of combined muscle layer thickness of rectus femoris and vastus intermedius (cm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of vastus lateralis - change in muscle layer thickness (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement of the thickness of the vastus lateralis between the superficial and deep aponeuroses (cm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of vastus lateralis - change in fascicle pennation angle (degrees)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement of the pennation angle of the muscle fascicles as they insert into the deep aponeuroses of the vastus lateralis muscle (degrees)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of vastus lateralis - change in fascicle length (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>This is a single measure, derived by trigonometry (the Sine of the pennation angle multiplied by the muscle thickness).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of the medial head of gastrocnemius - change in muscle thickness (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement of the thickness of the medial head of the gastrocnemius between the superficial and deep aponeuroses (cm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of the medial head of gastrocnemius - change in fascicle pennation angle (degrees)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement of the pennation angle of the muscle fascicles as they insert into the deep aponeuroses of the medial head of gastrocnemius (angles)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of the medial head of gastrocnemius - change in fascicle length (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>This is single measure which is mathematically derived by trigonometry using the known pennation angle (degrees) and thickness (cm): the Sine of the pennation angle multiplied by the muscle thickness.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of the rectus abdominis muscle - change in muscle layer thickness (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Measurement of rectus abdominis muscle layer thickness - (cm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Diaphragm thickness assessment by ultrasound - change in end expiratory thickness (mm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Assessment of thickness at end expiration (mm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Diaphragm thickness assessment by ultrasound - change in end inspiratory thickness (mm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Assessment of thickness at end inspiration (mm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Diaphragm thickness assessment by ultrasound - change in thickening fraction (%)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Assessment of thickening fraction, derived mathematically from thicknesses at inspiration and expiration (%)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ultrasound assessment of change in diaphragmatic excursion (cm)</measure>
    <time_frame>Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.</time_frame>
    <description>Assessment of maximal excursion of diaphragm, measured with M-mode ultrasonography (mm)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Measurement of change in blood biomarkers (microRNA analysis for markers of muscle loss, expressed as a percentage fold increase/decrease compared to baseline).</measure>
    <time_frame>Samples taken on days 1, 5, 10 and 14</time_frame>
    <description>Blood samples taken during the study period and analysed for markers of muscle loss/degradation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of change in urinary biomarkers (microRNA analysis for markers of muscle loss, expressed as a percentage-fold increase/decrease compared to baseline).</measure>
    <time_frame>Samples taken on days 1, 5, 10 and 14</time_frame>
    <description>Blood and urine samples taken during the study period and analysed for markers of muscle loss/degradation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of the number of biomarkers expressed from muscle biopsies (microRNA analysis for markers of muscle loss, expressed as the number and type of micro-RNAs expressed within the samples).</measure>
    <time_frame>Samples taken on day 1 and 14</time_frame>
    <description>Muscle biopsy samples taken during the study period and analysed for markers of muscle loss/degradation. Number and type of micro-RNAs to be noted).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of muscle fibre cross sectional area from muscle biopsies (mm2)</measure>
    <time_frame>Samples taken on day 1 and 14</time_frame>
    <description>Histological staining and analysis of muscle fibre composition, expressed in square millimetres and as a percentage-fold increase/decrease compared to baseline).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follow up testing - Distance achieved in a 6 minute walk test, metres)</measure>
    <time_frame>At 3 month follow up</time_frame>
    <description>Distance achieved during a 6 minute shuttle walk of 20 metres length</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follow up testing - Hand grip dynamometry (hand grip strength, Newtons)</measure>
    <time_frame>At 3 month follow up</time_frame>
    <description>Strength of hand grip in both hands</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follow up - Lower limb strength assessment - Force generated at maximal contraction for knee extension (Newtons)</measure>
    <time_frame>At 3 month follow up</time_frame>
    <description>Strength of extension at the knee in both legs using a hand held dynamometry device (microFET 2 wireless device). Measured in Newtons.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follow up testing - Balance assessment - Comparison of changes in center of pressure on a pressure plate.</measure>
    <time_frame>At 3 month follow up</time_frame>
    <description>Comparison of changes in centre of pressure on a pressure plate. The centre of pressure is measured over 20 seconds with the participant standing still. Maximal variation in lateral and anterior-posterior sway is recorded by the pressure plate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follow up testing - Psychological assessment - Comparison of total scores obtained from the SF-36 questionnaire (maximum score 100, minimum score zero).</measure>
    <time_frame>At 3 month follow up</time_frame>
    <description>Comparison of scores obtained from the SF-36 questionnaire between the two groups. A lower score indicates greater disability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follow Up - Maximal Inspiratory Pressure monitoring in kilopascals (kPa)</measure>
    <time_frame>At 3 month follow up</time_frame>
    <description>Using the Power Breathe K2 device</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of delirium during the trial period - using the CAM-ICU tool.</measure>
    <time_frame>Days 1-14</time_frame>
    <description>Assessed by twice daily Cambridge Assessment Method for the ICU (CAM-ICU) assessments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of renal replacement therapy during the trial period</measure>
    <time_frame>Days 1-14</time_frame>
    <description>Daily monitoring to see if patient has required renal replacement therapy (defined as either haemofiltration or haemodialysis).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total dose of noradrenaline given per day</measure>
    <time_frame>Day 1-14</time_frame>
    <description>Daily monitoring of doses of inotropic and vasopressor drugs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall fluid balance (in mls) at the end of each study day</measure>
    <time_frame>Day 1-14</time_frame>
    <description>Daily noting of 24 hour fluid balance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Insulin doses (in international units) required per day</measure>
    <time_frame>Day 1-14</time_frame>
    <description>Daily monitoring of exogenous insulin requirements</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood glucose concentration (mmol/L)</measure>
    <time_frame>Day 1-14</time_frame>
    <description>Daily monitoring of glucose levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate variability</measure>
    <time_frame>Days 1 - 14 but only on the days where cycling takes place (ten sessions)</time_frame>
    <description>Measured via a wireless skin patch</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety - number of times an endotracheal/tracheostomy tube is dislodged during the cycling sessions</measure>
    <time_frame>Days 1 - 14 but only on the days where cycling takes place (ten sessions)</time_frame>
    <description>Expressed as a simple count of how many times an airway device dislodges</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety - number of times an nasogastric tube is dislodged during the cycling sessions</measure>
    <time_frame>Days 1 - 14 but only on the days where cycling takes place (ten sessions).</time_frame>
    <description>Expressed as a simple count of how many times a nasogastric feed tube dislodges.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety - number of times an a central or arterial line device is dislodged during the cycling sessions</measure>
    <time_frame>Days 1 - 14 but only on the days where cycling takes place (ten sessions).</time_frame>
    <description>Expressed as a simple count of how many times a central or arterial line dislodges.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Muscle Weakness</condition>
  <arm_group>
    <arm_group_label>Cycling with FES</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ten sessions of 14 days in patients consented within 48 hours of arriving in critical care who are sedated and mechanically ventilated with a diagnosis of sepsis from any source.&#xD;
Sessions last a maximum of 30 minutes (with an ideal minimum of 20 minutes), using the Restorative Therapies (RT) 300 Supine with the Sage 12-channel stimulator. Stimulation will provided to the quadriceps, hamstrings, calves and abdomen. Both legs and both sides of the abdomen will be stimulated. Stimulation current settings are individualised for each patient and each muscle group.&#xD;
These patients will also receive their routine physiotherapy that they would have received if they were in the control group (or not in the trial at all).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control - routine physiotherapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Usual daily physiotherapy, consisting of limb care and mobilisation, and respiratory care and exercises as appropriate.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Cycling with FES</intervention_name>
    <description>As described already</description>
    <arm_group_label>Cycling with FES</arm_group_label>
    <other_name>RT-300 Supine</other_name>
    <other_name>Restorative Therapies</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Routine physiotherapy</intervention_name>
    <description>As described already</description>
    <arm_group_label>Control - routine physiotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients will be recruited in the Intensive Care Unit of the Royal Liverpool&#xD;
             University Hospital. All patients will be over 18, and have a critical illness that&#xD;
             requires mechanical ventilation with an initial period of sedation. This study will&#xD;
             focus on patients with a definite or suspected case of sepsis from any source.&#xD;
&#xD;
        Sepsis has been recently redefined as: &quot;Life threatening organ-dysfunction caused by&#xD;
        dysregulated host response to infection&quot; whilst septic shock has become a subset of sepsis,&#xD;
        defined as: &quot;circulatory and cellular/metabolic dysfunction associated with a higher risk&#xD;
        of mortality(44).&#xD;
&#xD;
        For the purposes of this study, a patient will be regarded as septic if they have evidence&#xD;
        of infection-related organ failure (e.g. sepsis-associated coagulopathy, altered mental&#xD;
        state, cardiovascular dysfunction, acute kidney injury, and altered liver function) and&#xD;
        require invasive mechanical ventilation with either definite or suspected evidence of&#xD;
        infection. This is to allow prompt treatment with FES rather than waiting for a positive&#xD;
        microbiological result to be obtained.&#xD;
&#xD;
        Within the definition of sepsis &quot;from any source&quot; a list of following is illustrative but&#xD;
        not exhaustive:&#xD;
&#xD;
          -  Urogenital sepsis (including urosepsis, pyelonephritis, endometritis and&#xD;
             chorioamnionitis)&#xD;
&#xD;
          -  Pneumonia (including community acquired, hospital acquired, and aspiration pneumonia.&#xD;
             Ventilator associated pneumonia would be excluded.)&#xD;
&#xD;
          -  Neurological infections such as encephalitis and meningitis.&#xD;
&#xD;
          -  Cellulitis, osteomyelitis and infections of soft tissue NOT affecting the lower limb.&#xD;
&#xD;
          -  Surgical infections, including post-operative laparotomy with evidence of peritoneal&#xD;
             soiling, and evidence of infection prior to the operation, in patients who require 2&#xD;
             or more organ system support after the operation.&#xD;
&#xD;
          -  Intra-abdominal sepsis, including biliary sepsis, hepatitis, and acute pancreatitis.&#xD;
             In the case of acute pancreatitis, evidence of infection is required to fulfil the&#xD;
             criteria. Acute pancreatitis with sterile tissue/fluid samples would not be suitable.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients under 18&#xD;
&#xD;
          -  Patients who decline consent&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Neuromuscular disease&#xD;
&#xD;
          -  Rhabdomyolysis&#xD;
&#xD;
          -  Lower limb trauma&#xD;
&#xD;
          -  Patients unlikely to survive to 96 hours post admission&#xD;
&#xD;
          -  Consent unobtainable within 48 hours of admission&#xD;
&#xD;
          -  Morbid obesity (BMI&gt;40).&#xD;
&#xD;
          -  Presence of a pacemaker or Implantable Cardiac Defibrillator (ICD).&#xD;
&#xD;
          -  Unlikely to be mechanically ventilated for more than 48 hours.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ingeborg D Welters</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Liverpool</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Intensive Care Unit, Royal Liverpool University Hospital</name>
      <address>
        <city>Liverpool</city>
        <zip>L7 8XP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>October 15, 2018</study_first_submitted>
  <study_first_submitted_qc>December 6, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>November 3, 2020</last_update_submitted>
  <last_update_submitted_qc>November 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Liverpool</investigator_affiliation>
    <investigator_full_name>Ingeborg Welters</investigator_full_name>
    <investigator_title>Senior Lecturer, Institute of Aging and Chronic Disease</investigator_title>
  </responsible_party>
  <keyword>ICU acquired weakness (ICU-AW)</keyword>
  <keyword>FES</keyword>
  <keyword>Functional Electrical Stimulation</keyword>
  <keyword>Rehabilitation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscle Weakness</mesh_term>
    <mesh_term>Muscular Atrophy</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Translational research will take place in the Institute of Aging and Chronic Disease. Only the participant number of the sample will be shared with any staff working with tissue samples.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 15, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/42/NCT03770442/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>August 30, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03770442
org study id: UoL001367
nct id: NCT03770442
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
Muscle wasting is a common consequence of critical illness, and has a profound impact upon
      the rehabilitation of those who survive admission to critical to care. The investigators
      intend to assess if the application of 10 sessions over two weeks of passive cycling with
      electrical stimulation to the lower limbs and abdomen can prevent muscle loss, or at least
      cause less muscle loss, compared to patients who receive standard daily sessions of
      physiotherapy. This will be done by comparing the changes in muscle size on ultrasound
      between the two groups, comparing functional measures at a 3 month follow up, and by
      performing translational research using tissue samples taken during the study.
Patients are mechanically ventilated and sedated with a diagnosis of sepsis (from any source)
      will be eligible for this study. Provided they meet the inclusion criteria, they will be
      randomised within 48 hours of admission, to either ten 30 minute sessions of passive cycling
      with functional electrical stimulation (FES) to the thighs, hamstrings, calves and abdomen
      over a 14 day period, or to a control group of routine physiotherapy. The trial group will
      also receive this physiotherapy.

      On admission to the study, all patients will receive on day 1:

      Ultrasound measurements of:

      Rectus femoris cross-sectional area Thickness of rectus femoris and vastus intermedius
      Thickness, pennation angle and derived fascicle length of vastus lateralis and medial head of
      gastrocnemius Thickness of rectus abdominis. Thickness of diaphragm

      A blood sample taken from an arterial line A urine sample taken from a urinary catheter A
      muscle biopsy taken from the right vastus lateralis

      They will then receive ten 30 minute sessions of passive cycling with functional electrical
      stimulation over 14 days, or a control group will receive routine physiotherapy during this
      period.

      Repeat ultrasounds will be taken at days 3, 5, 7, 10 and 14. Repeat blood and urine sampling
      at days 5, 10 and 14. Repeat muscle biopsy at day 14.

      All cycling, ultrasounds and tissue sampling will end on day 14 regardless of the ventilator
      status of the patient.

      In patients who survive to be discharged from critical care, they will be followed up at 3
      months for:

      Repeat ultrasound scan of all muscles listed Six minute walk test Hand grip and lower limb
      dynamometry, Balance testing (by standing upright on a pressure plate for 20 seconds)
      Psychological assessment using the 36 item Short Form (SF-36) questionnaire

      Tissue sampling will be stored in the University of Liverpool for analysis of biomarkers of
      muscle damage and loss between the two groups.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
masking description: Ultrasound images will be labelled by their participant number, and not by intervention. Therefore, when image analysis takes place, the investigators will not know whether the images come from somebody who received cycling sessions or the control group.
Tissue samples will be treated in the same way.
In follow up sessions, participants will be asked not to reveal if they can remember whether they cycled or not.
measure: Ultrasound assessment of rectus femoris - Change in cross sectional area (cm2)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement of cross-sectional area of rectus femoris (cm2)
measure: Ultrasound assessment of rectus femoris - Change in muscle layer thickness (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement on muscle layer thickness of rectus femoris (cm)
measure: Ultrasound assessment of anterior thigh musculature - Change in muscle layer thickness (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement of combined muscle layer thickness of rectus femoris and vastus intermedius (cm)
measure: Ultrasound assessment of vastus lateralis - change in muscle layer thickness (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement of the thickness of the vastus lateralis between the superficial and deep aponeuroses (cm)
measure: Ultrasound assessment of vastus lateralis - change in fascicle pennation angle (degrees)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement of the pennation angle of the muscle fascicles as they insert into the deep aponeuroses of the vastus lateralis muscle (degrees)
measure: Ultrasound assessment of vastus lateralis - change in fascicle length (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: This is a single measure, derived by trigonometry (the Sine of the pennation angle multiplied by the muscle thickness).
measure: Ultrasound assessment of the medial head of gastrocnemius - change in muscle thickness (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement of the thickness of the medial head of the gastrocnemius between the superficial and deep aponeuroses (cm)
measure: Ultrasound assessment of the medial head of gastrocnemius - change in fascicle pennation angle (degrees)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement of the pennation angle of the muscle fascicles as they insert into the deep aponeuroses of the medial head of gastrocnemius (angles)
measure: Ultrasound assessment of the medial head of gastrocnemius - change in fascicle length (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: This is single measure which is mathematically derived by trigonometry using the known pennation angle (degrees) and thickness (cm): the Sine of the pennation angle multiplied by the muscle thickness.
measure: Ultrasound assessment of the rectus abdominis muscle - change in muscle layer thickness (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Measurement of rectus abdominis muscle layer thickness - (cm)
measure: Diaphragm thickness assessment by ultrasound - change in end expiratory thickness (mm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Assessment of thickness at end expiration (mm)
measure: Diaphragm thickness assessment by ultrasound - change in end inspiratory thickness (mm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Assessment of thickness at end inspiration (mm)
measure: Diaphragm thickness assessment by ultrasound - change in thickening fraction (%)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Assessment of thickening fraction, derived mathematically from thicknesses at inspiration and expiration (%)
measure: Ultrasound assessment of change in diaphragmatic excursion (cm)
time frame: Ultrasounds taken on day 1, 3, 5, 7, 10 and 14, and at 3 month follow up.
description: Assessment of maximal excursion of diaphragm, measured with M-mode ultrasonography (mm)
measure: Measurement of change in blood biomarkers (microRNA analysis for markers of muscle loss, expressed as a percentage fold increase/decrease compared to baseline).
time frame: Samples taken on days 1, 5, 10 and 14
description: Blood samples taken during the study period and analysed for markers of muscle loss/degradation
measure: Measurement of change in urinary biomarkers (microRNA analysis for markers of muscle loss, expressed as a percentage-fold increase/decrease compared to baseline).
time frame: Samples taken on days 1, 5, 10 and 14
description: Blood and urine samples taken during the study period and analysed for markers of muscle loss/degradation
measure: Measurement of the number of biomarkers expressed from muscle biopsies (microRNA analysis for markers of muscle loss, expressed as the number and type of micro-RNAs expressed within the samples).
time frame: Samples taken on day 1 and 14
description: Muscle biopsy samples taken during the study period and analysed for markers of muscle loss/degradation. Number and type of micro-RNAs to be noted).
measure: Measurement of muscle fibre cross sectional area from muscle biopsies (mm2)
time frame: Samples taken on day 1 and 14
description: Histological staining and analysis of muscle fibre composition, expressed in square millimetres and as a percentage-fold increase/decrease compared to baseline).
measure: Follow up testing - Distance achieved in a 6 minute walk test, metres)
time frame: At 3 month follow up
description: Distance achieved during a 6 minute shuttle walk of 20 metres length
measure: Follow up testing - Hand grip dynamometry (hand grip strength, Newtons)
time frame: At 3 month follow up
description: Strength of hand grip in both hands
measure: Follow up - Lower limb strength assessment - Force generated at maximal contraction for knee extension (Newtons)
time frame: At 3 month follow up
description: Strength of extension at the knee in both legs using a hand held dynamometry device (microFET 2 wireless device). Measured in Newtons.
measure: Follow up testing - Balance assessment - Comparison of changes in center of pressure on a pressure plate.
time frame: At 3 month follow up
description: Comparison of changes in centre of pressure on a pressure plate. The centre of pressure is measured over 20 seconds with the participant standing still. Maximal variation in lateral and anterior-posterior sway is recorded by the pressure plate.
measure: Follow up testing - Psychological assessment - Comparison of total scores obtained from the SF-36 questionnaire (maximum score 100, minimum score zero).
time frame: At 3 month follow up
description: Comparison of scores obtained from the SF-36 questionnaire between the two groups. A lower score indicates greater disability.
measure: Follow Up - Maximal Inspiratory Pressure monitoring in kilopascals (kPa)
time frame: At 3 month follow up
description: Using the Power Breathe K2 device
measure: Incidence of delirium during the trial period - using the CAM-ICU tool.
time frame: Days 1-14
description: Assessed by twice daily Cambridge Assessment Method for the ICU (CAM-ICU) assessments
measure: Incidence of renal replacement therapy during the trial period
time frame: Days 1-14
description: Daily monitoring to see if patient has required renal replacement therapy (defined as either haemofiltration or haemodialysis).
measure: Total dose of noradrenaline given per day
time frame: Day 1-14
description: Daily monitoring of doses of inotropic and vasopressor drugs
measure: Overall fluid balance (in mls) at the end of each study day
time frame: Day 1-14
description: Daily noting of 24 hour fluid balance
measure: Total Insulin doses (in international units) required per day
time frame: Day 1-14
description: Daily monitoring of exogenous insulin requirements
measure: Blood glucose concentration (mmol/L)
time frame: Day 1-14
description: Daily monitoring of glucose levels
measure: Heart rate variability
time frame: Days 1 - 14 but only on the days where cycling takes place (ten sessions)
description: Measured via a wireless skin patch
measure: Safety - number of times an endotracheal/tracheostomy tube is dislodged during the cycling sessions
time frame: Days 1 - 14 but only on the days where cycling takes place (ten sessions)
description: Expressed as a simple count of how many times an airway device dislodges
measure: Safety - number of times an nasogastric tube is dislodged during the cycling sessions
time frame: Days 1 - 14 but only on the days where cycling takes place (ten sessions).
description: Expressed as a simple count of how many times a nasogastric feed tube dislodges.
measure: Safety - number of times an a central or arterial line device is dislodged during the cycling sessions
time frame: Days 1 - 14 but only on the days where cycling takes place (ten sessions).
description: Expressed as a simple count of how many times a central or arterial line dislodges.
arm group label: Cycling with FES
arm group type: Experimental
description: Ten sessions of 14 days in patients consented within 48 hours of arriving in critical care who are sedated and mechanically ventilated with a diagnosis of sepsis from any source.
Sessions last a maximum of 30 minutes (with an ideal minimum of 20 minutes), using the Restorative Therapies (RT) 300 Supine with the Sage 12-channel stimulator. Stimulation will provided to the quadriceps, hamstrings, calves and abdomen. Both legs and both sides of the abdomen will be stimulated. Stimulation current settings are individualised for each patient and each muscle group.
These patients will also receive their routine physiotherapy that they would have received if they were in the control group (or not in the trial at all).
arm group label: Control - routine physiotherapy
arm group type: Active Comparator
description: Usual daily physiotherapy, consisting of limb care and mobilisation, and respiratory care and exercises as appropriate.
intervention type: Device
intervention name: Cycling with FES
description: As described already
arm group label: Cycling with FES
other name: RT-300 Supine
other name: Restorative Therapies
intervention type: Other
intervention name: Routine physiotherapy
description: As described already
arm group label: Control - routine physiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Ingeborg D Welters
role: Principal Investigator
affiliation: University of Liverpool
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Liverpool
investigator full name: Ingeborg Welters
investigator title: Senior Lecturer, Institute of Aging and Chronic Disease
mesh term: Muscle Weakness
mesh term: Muscular Atrophy
sharing ipd: No
ipd description: Translational research will take place in the Institute of Aging and Chronic Disease. Only the participant number of the sample will be shared with any staff working with tissue samples.
provided document: 
submitted: August 30, 2023