<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/NCT04412200</url>
  </required_header>
  <id_info>
    <org_study_id>0290-19-ASF</org_study_id>
    <nct_id>NCT04412200</nct_id>
  </id_info>
  <brief_title>Efficacy of Hyperbaric Oxygen Therapy (HBOT) in New-onset Type-1 Diabetes Mellitus</brief_title>
  <official_title>Randomized Controlled Study to Evaluate the Effect of Hyperbaric Oxygen Therapy (HBOT) on Treg-CD4+Cells, Cytokines Profile, and Beta Cells Reserve in New-onset Type-1 Diabetes Mellitus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assaf-Harofeh Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assaf-Harofeh Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Type 1 Diabetes Mellitus (T1DM) is caused by an autoimmune process that progressively&#xD;
      destroys the pancreatic β-cells, and leads to dependence on multiple daily insulin&#xD;
      subcutaneous injections according to glucose measurements and dietary restrictions, leading&#xD;
      to short and long term complications. Current data demonstrate that even modest preservation&#xD;
      of β-cell function and endogenous production of insulin (marked by C-peptide) may result in&#xD;
      meaningful clinical benefits including lower rates of complications, improved metabolic&#xD;
      control, reduced insulin injections, and improved quality of life.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
        1. To assess the effect of HBOT on Treg, mesanchymal stem cells, and pro-inflammatory&#xD;
           cytokines ratio in pediatric population with new-onset T1DM Secondary&#xD;
&#xD;
        2. To assess the effect of HBOT on beta cell reserve in pediatric population with new-onset&#xD;
           T1DM&#xD;
&#xD;
        3. To assess the effect of HBOT on glycemic control parameters including time in range,&#xD;
           HbA1c and daily insulin dose, in the pediatric population with new-onset T1DM&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      Randomized, controlled study of pediatric and young adults patients who have been newly&#xD;
      diagnosed with type 1 diabetes within 12 weeks prior to randomization (4-6 weeks from&#xD;
      screening) and express peak C-peptide ≥ 0.2 pmol/ml Subjects will be randomized to hyperbaric&#xD;
      oxygen chamber (HBOC) group and to a non-intervention, control group. Both groups will be&#xD;
      managed similarly by carbohydrate counting and basal bolus insulin administration, based on&#xD;
      their interstitial glucose levels by glucose continuous glucose monitoring system (CGMS) and&#xD;
      carbohydrate counting before meals.&#xD;
&#xD;
      The intervention protocol includes 12 weeks of intensive management, and 12 weeks of follow&#xD;
      up.&#xD;
&#xD;
      During the intensive management period - for 12 weeks, the HBOC group will receive 100%&#xD;
      oxygen at 2 ATA for 90 min with 5 min air breaks every 20 min at each session. Intensive&#xD;
      management period includes 60 daily sessions, 5 days per week within 12 weeks, During the&#xD;
      intensive management period - for 12 weeks, the control group will receive common practice&#xD;
      managemnt.&#xD;
&#xD;
      All will be instructed to inject insulin pre-meals according to carbs-counting, and CGMS.&#xD;
      Insulin will be administered by subcutaneous continuous insulin infusion (SCII) or by pens&#xD;
      with CLIPSULIN only, for accurate daily dose of insulin recording.&#xD;
&#xD;
      Along the 24 weeks of the study several parameters will be assessed at pre-defined time&#xD;
      points .&#xD;
&#xD;
        1. Immune system parameters will be assessed by blood levels of T-regulatory cells,&#xD;
           diabetes auto-antibody and inflammatory cytokines.&#xD;
&#xD;
        2. Pancreatic β cells function will be evaluated by measurements of blood area under the&#xD;
           curve (AUC) C-peptide, peak C-peptide, and basal proinsulin/c-peptide ratio.&#xD;
&#xD;
        3. glycemic control parameters will be evaluated by CGMS data regarding time spent in&#xD;
           glycemic range, hypoglycemic and hyperglycemic ranges, total daily dose of insulin&#xD;
           according to CLIPSULIN , and blood tests for glycated hemoglobin (HbA1c).&#xD;
&#xD;
        4. Microbiome changes will be assessed by stool samples.&#xD;
&#xD;
      Expected significance: the study suggests a safe modality used clinically among adults and&#xD;
      other paediatric conditions, for the possible solution of an unmet urgent medical need,&#xD;
      studied successfully in an animal model. The study is designed to be powered to answer the&#xD;
      question of efficacy, and in addition, addresses the mechanisms by which it may halt the&#xD;
      progression of β cell destruction in new onset T1DM.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Anticipated">May 2026</completion_date>
  <primary_completion_date type="Anticipated">November 2024</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Regulatory T cells and B cells</measure>
    <time_frame>24 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Cytokine secretion</measure>
    <time_frame>24 weeks</time_frame>
    <description>by stimulated peripheral blood mononuclear cells cultured with LPS or PHA for 72 hours, and in supernatant will be measured by relevant commercial ELISA kits</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>insulin daily dose (IDD) unit/kg/d</measure>
    <time_frame>24 weeks</time_frame>
    <description>Difference between groups in achievement of glycemic targets according to ITDD, with a lower ITDD. assessed by: mean and SD of glucose, CV, time spent in range &gt;70%, and time spent at hypoglycemic range &lt; 1% at end of treatment periods, IDD according to weight.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-max of stimulated C peptide</measure>
    <time_frame>24 weeks</time_frame>
    <description>Difference between treatment groups (HBOT/SHBC) in change of β cell function (measured by C-max of stimulated C peptide) from screening to end of study (24 weeks).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC of stimulated C peptide</measure>
    <time_frame>24 weeks</time_frame>
    <description>Difference between treatment groups (HBOT/SHBC) in change of β cell function (measured by AUC of stimulated C peptide) from screening to end of study (24 weeks).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>T1DM</condition>
  <arm_group>
    <arm_group_label>Hyperbaric oxygen chamber Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be randomized at a ratio of 2:1, to hyperbaric chamber (100% oxygen at 2 ATA)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>control group will receive common practice management.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Hyperbaric oxygen chamber (HBOC)</intervention_name>
    <description>HBOC group will receive 100% oxygen at 2 ATA for 90 min with 5 min air breaks every 20 min at each session. Intensive management period includes 60 daily sessions, 5 days per week within 12 weeks,</description>
    <arm_group_label>Hyperbaric oxygen chamber Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Parent/guardian willing and able to sign an informed consent&#xD;
&#xD;
          -  Participant willing and able to sign an assent&#xD;
&#xD;
          -  Diagnosed with type 1 diabetes within 12 weeks prior to randomization&#xD;
&#xD;
          -  Treated with insulin by basal-bolus regimen (injections or pump)&#xD;
&#xD;
          -  Peak C-peptide ≥ 0.2 pmol/ml&#xD;
&#xD;
          -  At least 1 positive diabetes auto-antibody&#xD;
&#xD;
          -  No significant abnormalities in hematology and serum chemistry according to the&#xD;
             investigator's judgment, taking into consideration the potential effects of the&#xD;
             diabetic illness&#xD;
&#xD;
          -  No significant abnormalities in urinalysis, taking into considerations the potential&#xD;
             effects of the diabetic illness&#xD;
&#xD;
          -  For females of child bearing potential: whose screening pregnancy test is negative and&#xD;
             who are using contraceptive methods deemed reliable by the investigator&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Planned major surgery within the study period&#xD;
&#xD;
          -  Clinically significant inter-current illnesses, including (but not limited to): lung,&#xD;
             cardiac, hepatic, renal, eye, neurological, hematological, neoplastic, immunological,&#xD;
             skeletal or other, that in the opinion of the investigator, could interfere with the&#xD;
             safety, compliance or other aspects of this study. Patients with well-controlled,&#xD;
             chronic diseases could be possibly included after consultation with the investigator&#xD;
             at site.&#xD;
&#xD;
          -  Presence of psychiatric/ mental disorder or any other medical disorder which might&#xD;
             impair the patient's ability to give informed consent or to comply with the&#xD;
             requirements of the study protocol&#xD;
&#xD;
          -  Participation in another interventional clinical trial&#xD;
&#xD;
          -  Inability to attend scheduled clinic visits and/or comply with the study protocol&#xD;
&#xD;
          -  Current use of any medication known to influence glucose tolerance (e.g., β-blockers,&#xD;
             angiotensin-converting enzyme inhibitors, interferons, quinidine anti-malarial drugs,&#xD;
             lithium, niacin, metformin, sulfonylureas, glinides, thiazolidinediones, exenatide,&#xD;
             liraglutide, DPP-IV inhibitors or amylin).&#xD;
&#xD;
          -  Lung disease, middle ear disease, inner ear disease, history of epileptic seizures or&#xD;
             any other condition that based on the physician clinical judgment is not suitable to&#xD;
             get the hyperbaric treatment.&#xD;
&#xD;
          -  Any other factor that, in the opinion of the investigator, would prevent the patient&#xD;
             form complying with the requirements of the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Marianna Rachmiel</last_name>
    <phone>0537346636</phone>
    <email>rmarianna@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Asaf harofe medical center</name>
      <address>
        <city>Tzrifin</city>
        <zip>70300</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Avital Leshem</last_name>
      <phone>0528303012</phone>
      <email>childendo.research@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Assaf Haroffeh Medical center</name>
      <address>
        <city>Zrifin</city>
        <zip>70300</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marianna Rachmiel, md</last_name>
      <phone>972-8-9542007</phone>
      <email>mariannar@asaf.health.gov.il</email>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 2, 2020</study_first_posted>
  <last_update_submitted>September 18, 2022</last_update_submitted>
  <last_update_submitted_qc>September 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Hyperbaric chamber</keyword>
  <keyword>autoimmune disease</keyword>
  <keyword>inflammation</keyword>
  <keyword>recent onset autoimmune diabetes</keyword>
  <keyword>beta cells</keyword>
  <keyword>diabetes mellitus type 1</keyword>
  <keyword>pediatrics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <!-- 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/NCT04412200
org study id: 0290-19-ASF
nct id: NCT04412200
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Type 1 Diabetes Mellitus (T1DM) is caused by an autoimmune process that progressively
      destroys the pancreatic β-cells, and leads to dependence on multiple daily insulin
      subcutaneous injections according to glucose measurements and dietary restrictions, leading
      to short and long term complications. Current data demonstrate that even modest preservation
      of β-cell function and endogenous production of insulin (marked by C-peptide) may result in
      meaningful clinical benefits including lower rates of complications, improved metabolic
      control, reduced insulin injections, and improved quality of life.

      Objective:

        1. To assess the effect of HBOT on Treg, mesanchymal stem cells, and pro-inflammatory
           cytokines ratio in pediatric population with new-onset T1DM Secondary

        2. To assess the effect of HBOT on beta cell reserve in pediatric population with new-onset
           T1DM

        3. To assess the effect of HBOT on glycemic control parameters including time in range,
           HbA1c and daily insulin dose, in the pediatric population with new-onset T1DM

      Study design:

      Randomized, controlled study of pediatric and young adults patients who have been newly
      diagnosed with type 1 diabetes within 12 weeks prior to randomization (4-6 weeks from
      screening) and express peak C-peptide ≥ 0.2 pmol/ml Subjects will be randomized to hyperbaric
      oxygen chamber (HBOC) group and to a non-intervention, control group. Both groups will be
      managed similarly by carbohydrate counting and basal bolus insulin administration, based on
      their interstitial glucose levels by glucose continuous glucose monitoring system (CGMS) and
      carbohydrate counting before meals.

      The intervention protocol includes 12 weeks of intensive management, and 12 weeks of follow
      up.

      During the intensive management period - for 12 weeks, the HBOC group will receive 100%
      oxygen at 2 ATA for 90 min with 5 min air breaks every 20 min at each session. Intensive
      management period includes 60 daily sessions, 5 days per week within 12 weeks, During the
      intensive management period - for 12 weeks, the control group will receive common practice
      managemnt.

      All will be instructed to inject insulin pre-meals according to carbs-counting, and CGMS.
      Insulin will be administered by subcutaneous continuous insulin infusion (SCII) or by pens
      with CLIPSULIN only, for accurate daily dose of insulin recording.

      Along the 24 weeks of the study several parameters will be assessed at pre-defined time
      points .

        1. Immune system parameters will be assessed by blood levels of T-regulatory cells,
           diabetes auto-antibody and inflammatory cytokines.

        2. Pancreatic β cells function will be evaluated by measurements of blood area under the
           curve (AUC) C-peptide, peak C-peptide, and basal proinsulin/c-peptide ratio.

        3. glycemic control parameters will be evaluated by CGMS data regarding time spent in
           glycemic range, hypoglycemic and hyperglycemic ranges, total daily dose of insulin
           according to CLIPSULIN , and blood tests for glycated hemoglobin (HbA1c).

        4. Microbiome changes will be assessed by stool samples.

      Expected significance: the study suggests a safe modality used clinically among adults and
      other paediatric conditions, for the possible solution of an unmet urgent medical need,
      studied successfully in an animal model. The study is designed to be powered to answer the
      question of efficacy, and in addition, addresses the mechanisms by which it may halt the
      progression of β cell destruction in new onset T1DM.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Regulatory T cells and B cells
time frame: 24 weeks
measure: Cytokine secretion
time frame: 24 weeks
description: by stimulated peripheral blood mononuclear cells cultured with LPS or PHA for 72 hours, and in supernatant will be measured by relevant commercial ELISA kits
measure: insulin daily dose (IDD) unit/kg/d
time frame: 24 weeks
description: Difference between groups in achievement of glycemic targets according to ITDD, with a lower ITDD. assessed by: mean and SD of glucose, CV, time spent in range >70%, and time spent at hypoglycemic range < 1% at end of treatment periods, IDD according to weight.
measure: C-max of stimulated C peptide
time frame: 24 weeks
description: Difference between treatment groups (HBOT/SHBC) in change of β cell function (measured by C-max of stimulated C peptide) from screening to end of study (24 weeks).
measure: AUC of stimulated C peptide
time frame: 24 weeks
description: Difference between treatment groups (HBOT/SHBC) in change of β cell function (measured by AUC of stimulated C peptide) from screening to end of study (24 weeks).
arm group label: Hyperbaric oxygen chamber Arm
arm group type: Experimental
description: Patients will be randomized at a ratio of 2:1, to hyperbaric chamber (100% oxygen at 2 ATA)
arm group label: Control arm
arm group type: No Intervention
description: control group will receive common practice management.
intervention type: Device
intervention name: Hyperbaric oxygen chamber (HBOC)
description: HBOC group will receive 100% oxygen at 2 ATA for 90 min with 5 min air breaks every 20 min at each session. Intensive management period includes 60 daily sessions, 5 days per week within 12 weeks,
arm group label: Hyperbaric oxygen chamber Arm
criteria: 
gender: All
minimum age: 8 Years
maximum age: 21 Years
healthy volunteers: No
last name: Marianna Rachmiel
phone: 0537346636
email: rmarianna@gmail.com
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Israel
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1