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Mesenchymal Stem Cells in Patients With Type 1 Diabetes Mellitus

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ClinicalTrials.gov Identifier: NCT03920397
Recruitment Status : Enrolling by invitation
First Posted : April 18, 2019
Last Update Posted : April 23, 2019
Sponsor:
Information provided by (Responsible Party):
Débora Lopes Souto, Universidade Federal do Rio de Janeiro

Tracking Information
First Submitted Date  ICMJE April 5, 2019
First Posted Date  ICMJE April 18, 2019
Last Update Posted Date April 23, 2019
Actual Study Start Date  ICMJE March 1, 2015
Estimated Primary Completion Date March 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
  • Pancreatic β-cell function after an adipose tissue-derived stem/stromal cells infusion [ Time Frame: 24 months ]
    Thirth patients with recent-onset type 1 diabetes wil receive adipose tissue-derived stem/stromal cells (ASCs). The patients wil be admitte in the day of the infusion and wil discharge 24 hours after infusion. A single dose of ASCs wil be infuse in a peripheral upper arm vein during 15-20 minutes. Pancreatic β-cell function will be assess at each follow-up outpatient visit (1, 3, 6, 12, 18 and 24 months after the ASCs infusion). In each visit, C-Peptide wil be analyze by immunofluorometric assay, considering the time 0 (basal), and peak stimulated C-Peptide (30, 60, 90 and 120 minutes) after mixed meal test (Glucerna)
  • Glycemic control after an adipose tissue-derived stem/stromal cells [ Time Frame: 24 months ]
    Thirth patients with recent-onset type 1 diabetes wil receive adipose tissue-derived stem/stromal cells (ASCs). The patients wil be admitte in the day of the infusion and wil discharge 24 hours after infusion. A single dose of ASCs wil be infuse in a peripheral upper arm vein during 15-20 minutes. Frequency of hypoglycemia (%) insulin dose/kg, and blood samples will be drawn for the Glycated hemoglobin assessment (High Performance Liquid Chromatography by boronate affinity) at each follow-up outpatient visit (1, 3, 6, 12, 18 and 24 months after the ASCs infusion)
Original Primary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
  • Pancreatic β-cell function after an adipose tissue-derived stem/stromal cells infusion [ Time Frame: 24 months ]
    Thirth patients with recent-onset type 1 diabetes wil receive adipose tissue-derived stem/stromal cells (ASCs). The patients wil be admitte in the day of the infusion and wil discharge 24 hours after infusion. A single dose of ASCs wil be infuse in a peripheral upper arm vein during 15-20 minutes. Pancreatic β-cell function will be assess at each follow-up outpatient visit (T1, T3, T6, T12, T18, T24). In each visit,C-Peptide wil be analyze by immunofluorometric assay at T0 and T6 and T12 and T18 and T24, considering basal and peak stimulated C-Peptide after mixed meal test (Glucerna).
  • Glycemic control after an adipose tissue-derived stem/stromal cells [ Time Frame: 24 months ]
    Thirth patients with recent-onset type 1 diabetes wil receive adipose tissue-derived stem/stromal cells (ASCs). The patients wil be admitte in the day of the infusion and wil discharge 24 hours after infusion. A single dose of ASCs wil be infuse in a peripheral upper arm vein during 15-20 minutes. Frequency of hypoglycemia (%) insulin dose/kg, and blood samples will be drawn for the Glycated hemoglobin assessment (High Performance Liquid Chromatography by boronate affinity) at each follow-up outpatient visit (T1, T3, T6, T12, T18, T24)
Change History Complete list of historical versions of study NCT03920397 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2019)
Oral cholecalciferol 2000UI/day supplementation [ Time Frame: 24 months ]
The same patients with recent-onset type 1 diabetes wil receive adipose tissue-derived stem/stromal cells (ASCs) will receive Oral cholecalciferol 2000UI/day supplementation for 24 months. The sérum 25-Hydroxy Vitamin D will be assess at each follow-up outpatient visit (1, 3, 6, 12, 18 and 24 months after the ASCs infusion) and C-Peptide wil be analyze by immunofluorometric assay, considering the time 0 (basal), and peak stimulated C-Peptide (30, 60, 90 and 120 minutes) after mixed meal test (Glucerna)
Original Secondary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
Oral cholecalciferol 2000UI/day supplementation [ Time Frame: 24 months ]
The same patients with recent-onset type 1 diabetes wil receive adipose tissue-derived stem/stromal cells (ASCs) will receive Oral cholecalciferol 2000UI/day supplementation for 24 months. The serum25 OH vitamin D will be assess at each follow-up outpatient visit (T1, T3, T6, T12, T18, T24) and C-Peptide wil be analyze by immunofluorometric assay at T0 and T6 and T12 and T18 and T24, considering basal and peak stimulated C-Peptide after mixed meal test (Glucerna).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mesenchymal Stem Cells in Patients With Type 1 Diabetes Mellitus
Official Title  ICMJE Allogenic Adipose Derived Mesenchymal Stem Cells and Vitamin D Supplementation in Patients With Recent-onset Type 1 Diabetes Mellitus
Brief Summary In this prospective, dual-center, open trial, patients with recent onset type 1 diabetes will receive one dose of allogenic Adipose tissue-derived stromal/stem cells (1x106 cells/kg) and oral cholecalciferol 2000UI/day for 24 months (group 1). They will be compare to patients that will receive just oral cholecalciferol 2000UI/day (group 2) and standard treatment (group 3: no treatment). Adverse events will be record. In addition, glycated hemoglobin, insulin dose, frequency of hypoglycemia, glycemic variability, % of time in hyper and hypoglycemia and peak response of the C-peptide after the mixed meal teste wil be measure at baseline (T0), after 3 (T3), 6 (T6), 12 (T12), 18 (T18), and 24 (T24) months.
Detailed Description

Adipose tissue samples will be obtain through liposuction procedures of three healthy volunteers undergoing aesthetic surgery at Clementino Fraga Filho (the hospital of Federal University of Rio de Janeiro, Brazil). Donors´sorology wil have to be negative for syphilis, Chagas disease, Hepatitis B virus, Hepatitis C, HIV 1 and 2, and Cytomegalovirus.

The adipose tissue-derived stem/stromal cells (ASCs) that wil be extract on healthy volunteers will be isolate, culture and samples will be process at Core Cell Technology of Pontifícia Universidade Católica do Paraná. Briefly, the procedures are:

  1. 100 ml of adipose tissue will be wash in sterile phosphate-buffered saline (Gibco Invitrogen). A one-step digestion by 1 mg/ml collagenase type I (Invitrogen) will be performe for 30 minutes at 37°C during permanent shaking, follow by filtration step through a 100 µm mesh filter (BD FALCON, BD Biosciences Discovery Labware, Bedford, MA, USA). The cell suspension will be centrifuge at 800 g for 10 minutes, and erythrocytes were removed by lysis buffer, pH 7.3.
  2. The remaining cells will be wash at 400 g for 10 minutes and then culture at a density of 1×105 cells/cm2 in T75 culture flasks and DMEM-F12 (Gibco Invitrogen) supplemente with 10% of fetal calf serum, penicillin (100 units/ml) and streptomycin (100 μg/ml). The culture medium will be replace three days after seeding, and then twice a week.
  3. ASCs will be subculture after reaching 80% confluence, with 0.5% trypsin/EDTA (Invitrogen) solution. Cells will be replate at a density of 4x103 cells/cm2 for expansion11A.
  4. Quality control of cell suspension sterility will be evaluate by tests to detect bacteria and fungi (Bact / Alert 3D, Biomerieux), endotoxins (Endosafe ™ PTS, Charles River) and Mycoplasma (KIT MycoAlert ™ PLUS Mycoplasma Detection, Lonza). Cell viability will be performe by flow cytometry using the vital dye 7-AAD (7-Aminoactinomycin D - BD#559925) to determine the percentage of viable cells and Annexin V protein (BD#51-65875X) to determine the percentage of cells in apoptosis. Cytogenetic analysis wil be performe by GTG-banding method.
  5. Cells will be phenotypically characterize by flow cytometry before the clinical application, using the following monoclonal antibodies: FITC-labeled CD14 (BD#555397), CD45 (BD#555482), CD19 (BD#555412), CD44 (BD#555478); PE-labeled CD73 (BD#550257), CD90 (BD#555596), CD166 (BD#559263), PerCP-labeled HLA-DR (BD#551375); APC-labeled CD34 (BD#555824), CD105 (BD#562408), CD29 (BD#559883) all purchased from BD (Pharmingen). At least 100.000 events wil bel acquire on a BD FACSCalibur™ flow cytometer (BD Biosciences), and data wil be analyzed using FlowJo 10 (TreeStar) software11A.

After the ASCs extraction, isolate, culture and process, the infusion in patients with recent-onset type 1 diabetes wil be according as describe bellow:

  1. At the day of infusion, ASCs monolayer wil be dissociate as described above and 1x106 cells/kg of the recipient patient wil be ressuspend in 5 ml of saline solution with 50% albumin and 5% anticoagulant citrate dextrose solution. Cell suspension wil send to the hospital in a cooler with recycled ice.
  2. Patients that wil receive ASCs wil be admitte to the hospital in the day of the infusion and wil discharge 24 hours after infusion. A single dose of ASCs wil be infuse in a peripheral upper arm vein during 15-20 minutes. Patients wil start takking oral cholecalciferol 2000 UI one day after the ASCs infusion.

Safety Tests: adverse events wil be record during the hospitalization (T0) and at each follow-up outpatient visit (3 [T3], 6 [T6], 12 [T12], 18 [T18], and 24 [T24] months after the ASCs infusion), with clinical and laboratory exams (blood count, lipids, renal and hepatic function, thyroid stimulating hormone, free tyroxine, antithyroglobulin antibody, calcium, phosphorus and 25-Hydroxy Vitamin D, performed with automated biochemical equipment CMD 800 IX1).

Clinical and Pancreatic Function Evaluation: Participants wil be followed for 24 months. On the first visit, all patients wil be interviewed and had a physical exam. Weight, height, body mass index (BMI), blood pressure, heart frequency, frequency of hypoglycemia and insulin dose/kg of body weight wil be evaluate in the first visit (T0) and after 1 (T1), 3 (T3), 6 (T6) 12 (T12) ,18 (18), and 24 (24) months.

Insulin dose adjustments wil be performe at each visit as necessary. All patients wil receive nutritional guidance according to American Diabetes Association recommendations.

Blood samples wil be drawn prio to ASCs infusion and at T1, T3, T6, T12, T18 and T24 for the measurement the Glycated hemoglobin (HbA1c. Method: High Performance Liquid Chromatography by boronate affinity). β-cell function wil be evaluated through C-Peptide measurement (Microparticle Chemiluminescent Immunoassay method, Architect Abbott) after a liquid mixed meal (Glucerna®), considering the time 0 (basal), 30, 60, 90 and 120 minutes. The area under the curve wil be calculate.

Comparison with previous case-control study using only vitamin D supplementation as intervention:

The investigators wil compare our results with patients previously included in a case-control study that investigated the effects of daily 2000 UI vitamin D without the infusion of cells in individuals with recent onset type 1 diabetes and similar age (> 15 years old), from a different population (São Paulo) in the same country region (Brazilian Southeast). Therefore, the investigators wil establish three different groups for comparison: 1) patients that wil receive ASCs + Vitamin D supplementation; 2) patients that wil receive only vitamin D supplementation; 3) patients that wil receive the conventional treatment for diabetes but any additional experimental treament (ASCs or Vitamin D).

Insulin dose adjustments or withdrawal wil be performed according to glycemic control. Changes in HbA1c, C-Peptide and insulin dose/kg of body weight wil be compare between groups. C-Peptide wil be analyze by immunofluorometric assay (AutoDelfia) at T0 and T6 and T12 and T18 and T24, considering basal and peak stimulated C-Peptide after mixed meal test (Glucerna).

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Patients with recent onset type 1 diabetes wil receive an dose of allogenic adipose tissue-derived stem/stromal cells (ASCs) and oral Cholecalciferol UI/day for 24 months.
Masking: None (Open Label)
Masking Description:
This is a open trial study.
Primary Purpose: Treatment
Condition  ICMJE Type 1 Diabetes Mellitus
Intervention  ICMJE Biological: Infusion of adipose tissue-derived stem/stromal cells and oral Cholecalciferol supplementation
The investigators will acess area under the curve of C-peptide after a liquid mixed meal (Glucerna®), considering the time 0 (basal), 30, 60, 90 and 120 minutes in each follow-up outpatient visit (3 [T3], 6 [T6], 12 [T12], 18 [T18], and 24 [T24] months after the adipose tissue-derived stem/stromal cells infusion). Other Clinical and Pancreatic Function Evaluation that wil be assess are: Weight, height, body mass index (BMI), blood pressure, heart frequency, frequency of hypoglycemia and insulin dose/kg of body weight, blood count, lipids, renal and hepatic function, thyroid stimulating hormone, free tyroxine, antithyroglobulin antibody, calcium, phosphorus and 25-Hydroxy Vitamin D.
Study Arms  ICMJE
  • Experimental: Adipose tissue-derived stem/stromal cells
    Safety of adipose tissue-derived stem/stromal cells (ASCs) for 24 months in patients with recente onset type 1 diabetes.
    Intervention: Biological: Infusion of adipose tissue-derived stem/stromal cells and oral Cholecalciferol supplementation
  • Experimental: Daily 2000 UI of daily oral cholecalciferol
    To investigate the efficacy of daily 2000 UI Cholecalciferol/day for 24 months in patients with recente onset type 1 diabetes.
    Intervention: Biological: Infusion of adipose tissue-derived stem/stromal cells and oral Cholecalciferol supplementation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: April 16, 2019)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2025
Estimated Primary Completion Date March 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of Type 1 Diabetes according to the American Diabetes Association criteria for a period less than four months.
  • Pancreatic Autoimmunity (positive anti-glutamic acid decarboxylase [GAD]; and/or Islet antigen 2 [anti-IA2]).

Exclusion Criteria:

  • Clinical evidence of malignancy or prior history.
  • Pregnancy or desire to become pregnant within 12 months of the study.
  • Breastfeeding .
  • HIV(+), Hepatitis B (+), Hepatitis C(+).
  • Diabetic ketoacidosis at diagnosis.
  • Glomerular filtration rate less than 60ml/min.
  • Use of immunosuppressors or glucocorticoids.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 35 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03920397
Other Study ID Numbers  ICMJE Nutro_MesenchymalStemCells_DM1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Débora Lopes Souto, Universidade Federal do Rio de Janeiro
Study Sponsor  ICMJE Universidade Federal do Rio de Janeiro
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Melanie Rodacki, Ph.D Universidade Federal do Rio de Janeiro
Study Director: Oliveira E.P José, Ph.D Universidade Federal do Rio de Janeiro
Study Director: Lenita Zajdenverg, Ph.D Universidade Federal do Rio de Janeiro
PRS Account Universidade Federal do Rio de Janeiro
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP