Efficacy of Hyperbaric Oxygen Therapy (HBOT) in New-onset Type-1 Diabetes Mellitus
Study Details
Study Description
Brief Summary
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: To assess the efficacy of HBOT on β- cell function in new-onset paediatric T1DM, compared with sham chamber, including mechanistic inestigation, Study design: A double blind, randomized, controlled study, recruiting patients ages 8-17 years, who have been diagnosed with T1DM within 12 weeks from randomization and express peak C-peptide ≥ 0.2 pmol/ml. Patients will be randomized at a ratio of 2:1, to hyperbaric chamber (100% oxygen at 2 ATA) or to sham chamber ( 21% oxygen at 1 ATA) in addition to clinical care guidelines. Both groups will receive a total of 108 sessions during the 52 weeks study. Primary outcome measures include stimulated peak C-peptide and area under the curve. Study includes also mechanistic exploratory analysis of proinsulin/insulin ratio, cytokines, Treg, mesenchymal stem cells analysis and pancreatic architecture study.
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
Background and preliminary results: 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. The autoimmune process is the result of genetic predisposition, immunological defects, and environmental factors concurring to development of autoreactive T cells (mostly T cytotoxic). 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. Hyperbaric oxygen therapy (HBOT) is a safe modality, consisting of inhalation of 100% oxygen at pressures exceeding 1 atmosphere absolute (ATA) in order to enhance the amount of oxygen dissolved in the body tissues. It has been demonstrated by our group and others, that the combined action of hyperoxia and hyperbaric pressure induces proliferation and mobilization of mesenchymal stem cells, and increment in circulating T regulatory cells (Treg). The effect of HBOT on T1DM pathophysiology was demonstrated in mouse model, increased number of insulin-positive cells compared with controls.
Hypothesis: management with HBOT at T1DM onset will have a beneficial effect on β cell preservation. The difference will be associated with higher mesenchymal cells production, increased Treg, and anti-inflammatory cytokine profile. Double blind, randomized, placebo controlled study of pediatric patients who have been newly diagnosed with type 1 diabetes within 12 weeks prior to randomization (6-8 weeks from screening) and express peak C-peptide ≥ 0.2 pmol/ml
Aims:
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To assess the efficacy of HBOT in preservation of β cell function in the pediatric population with new-onset T1DM
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To assess the efficacy of HBOT in achieving glycemic control parameters in target range with lower daily dose of insulin per weight, in the pediatric population with new-onset T1DM
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To assess the effect of HBOT on Treg, mesanchymal stem cells, and pro-inflammatory cytokines ratio in pediatric population with new-onset T1DM
Subjects will be randomized to hyperbaric oxygen chamber (HBOC) group and to a sham hyperbaric chamber (SHBC) group. Both groups will be managed similarly by moderate carbs diet and basal bolus insulin administration, based on their interstitial glucose levels by flash glucose continuous glucose monitoring system (FG-CGMS) and carbohydrate counting before meals.
The management protocol is divided to 3 periods: 12 weeks of intensive management, 12 weeks of maintenance management , and 25 weeks of follow up. Similar in both groups.
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 SHBC group will receive 21% oxygen at 1 ATA for 90 min with 5 min air breaks every 20 min at each session. In order to endure blinded sham treatment, in the first 5 minutes of each sessions, atmospheric pressure will increase to 1.2 ATA and then decompressed to 1 ATA. Intensive management period includes 60 daily sessions, 5 days per week within 12 weeks, During the maintenance management period, each group with receive 24 biweekly sessions within 12weeks . Each group will receive similar percent of oxygen and ATA as during intensive period.
During the management periods, patients will attend weekly meetings with the diabetes education team including dialectologist, nurse educator, psychologist and dietician. During follow-up period they will meet the team once a month.
All will be instructed not to exceed the amount of 80-120 gram of daily carbohydrates and to inject insulin pre-meals according to carbs-counting, and FG-CGMS. Insulin will be administered by subcutaneous continuous insulin infusion (SCII) or by InPen only, for accurate daily dose of insulin recording.
Along the 52 weeks of the study several parameters will be assessed at pre-defined time points .
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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.
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glycemic control parameters will be evaluated by FG-CGMS data regarding time spent in glycemicrange, hypoglycemic and hyperglycemic ranges, total daily dose of insulinaccording to InPen, and blood tests for glycated hemoglobin (HbA1c) and proteins.
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Immune system parameters will be assessed by blood levels of T-regulatory cells, diabetes auto-antibody and inflammatory cytokines.
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Microbiome changes will be assessed by stool samples.
Subjects ages 8-17 years old, diagnosed with type 1 diabetes in one of the diabetes management centers in Israel, up to 12 weeks prior to randomization.
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Parent/guardian willing and able to sign an informed consent 2. Participant willing and able to sign an assent 3. Diagnosed with type 1 diabetes within 12 weeks prior to randomization 4. Treated with insulin by basal-bolus regimen (injections or pump) 5. Peak C-peptide ≥ 0.2 pmol/ml 6. At least 1 positive diabetes auto-antibody 7. No significant abnormalities in hematology and serum chemistry according to the investigator's judgment, taking into consideration the potential effects of the diabetic illness 8. No significant abnormalities in urinalysis, taking into considerations the potential effects of the diabetic illness 9. For females of child bearing potential: whose screening pregnancy test is negative and who are using contraceptive methods deemed reliable by the investigator
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Planned major surgery within the study period
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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.
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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
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Participation in another interventional clinical trial
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Inability to attend scheduled clinic visits and/or comply with the study protocol
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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).
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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.
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Any other factor that, in the opinion of the investigator, would prevent the patient form complying with the requirements of the protocol.
Study Design
Arms and Interventions
| 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,
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| Sham Comparator: Sham hyperbaric chamber Arm Patients will be randomized at a ratio of 2:1, to Sham chamber (21% oxygen at 1 ATA) |
Device: sham Hyperbaric oxygen chamber (HBOC)
sham Hyperbaric oxygen chamber (HBOC)
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Outcome Measures
Primary Outcome Measures
- AUC of stimulated C peptide [52 weeks]
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 (52 weeks).
- C-max of stimulated C peptide [52 weeks]
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 (52 weeks).
Secondary Outcome Measures
- insulin daily dose (IDD) unit/kg/d [52 weeks]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Parent/guardian willing and able to sign an informed consent
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Participant willing and able to sign an assent
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Diagnosed with type 1 diabetes within 12 weeks prior to randomization
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Treated with insulin by basal-bolus regimen (injections or pump)
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Peak C-peptide ≥ 0.2 pmol/ml
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At least 1 positive diabetes auto-antibody
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No significant abnormalities in hematology and serum chemistry according to the investigator's judgment, taking into consideration the potential effects of the diabetic illness
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No significant abnormalities in urinalysis, taking into considerations the potential effects of the diabetic illness
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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:
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Planned major surgery within the study period
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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
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Inability to attend scheduled clinic visits and/or comply with the study protocol
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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).
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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.
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Any other factor that, in the opinion of the investigator, would prevent the patient form complying with the requirements of the protocol.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Assaf Harofeh MC
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 0290-19-ASF