Efficacy of Hyperbaric Oxygen Therapy (HBOT) in New-onset Type-1 Diabetes Mellitus

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

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.

Study Overview

• Status: Recruiting
• Conditions: T1DM
• Intervention / Treatment: Device: Hyperbaric oxygen chamber (HBOC)

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marianna Rachmiel; Phone Number: 0537346636; Email: rmarianna@gmail.com

Study Locations

• Israel
  • Tzrifin, Israel, 70300
    • Recruiting
    • Asaf Harofe Medical Center
    • Contact: Avital Leshem; Phone Number: 0528303012; Email: childendo.research@gmail.com
  • Zrifin, Israel, 70300
    • Recruiting
    • Assaf Haroffeh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Parent/guardian willing and able to sign an informed consent
• Participant willing and able to sign an assent
• Diagnosed with type 1 diabetes within 12 weeks prior to randomization
• Treated with insulin by basal-bolus regimen (injections or pump)
• Peak C-peptide ≥ 0.2 pmol/ml
• At least 1 positive diabetes auto-antibody
• No significant abnormalities in hematology and serum chemistry according to the investigator's judgment, taking into consideration the potential effects of the diabetic illness
• No significant abnormalities in urinalysis, taking into considerations the potential effects of the diabetic illness
• For females of child bearing potential: whose screening pregnancy test is negative and who are using contraceptive methods deemed reliable by the investigator

Exclusion Criteria:

• Planned major surgery within the study period
• Clinically significant inter-current illnesses, including (but not limited to): lung, cardiac, hepatic, renal, eye, neurological, hematological, neoplastic, immunological, skeletal or other, that in the opinion of the investigator, could interfere with the safety, compliance or other aspects of this study. Patients with well-controlled, chronic diseases could be possibly included after consultation with the investigator at site.
• Presence of psychiatric/ mental disorder or any other medical disorder which might impair the patient's ability to give informed consent or to comply with the requirements of the study protocol
• Participation in another interventional clinical trial
• Inability to attend scheduled clinic visits and/or comply with the study protocol
• Current use of any medication known to influence glucose tolerance (e.g., β-blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine anti-malarial drugs, lithium, niacin, metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors or amylin).
• Lung disease, middle ear disease, inner ear disease, history of epileptic seizures or any other condition that based on the physician clinical judgment is not suitable to get the hyperbaric treatment.
• Any other factor that, in the opinion of the investigator, would prevent the patient form complying with the requirements of the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Hyperbaric oxygen chamber Arm; Patients will be randomized at a ratio of 2:1, to hyperbaric chamber (100% oxygen at 2 ATA)	Device: Hyperbaric oxygen chamber (HBOC); 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,
NO_INTERVENTION: Control arm; control group will receive common practice management.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regulatory T cells and B cells		24 weeks
Cytokine secretion	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	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin daily dose (IDD) unit/kg/d	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.	24 weeks
C-max of stimulated C peptide	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).	24 weeks
AUC of stimulated C peptide	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).	24 weeks

Collaborators and Investigators

• Sponsor: Assaf-Harofeh Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2020
• Primary Completion (ANTICIPATED): November 1, 2024
• Study Completion (ANTICIPATED): May 1, 2026

Study Registration Dates

• First Submitted: May 29, 2020
• First Submitted That Met QC Criteria: June 1, 2020
• First Posted (ACTUAL): June 2, 2020

Study Record Updates

• Last Update Posted (ACTUAL): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 18, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: pediatrics; inflammation; autoimmune disease; beta cells; diabetes mellitus type 1; Hyperbaric chamber; recent onset autoimmune diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: 0290-19-ASF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No