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Minimal Islet Transplant at Diabetes Onset (MITO)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2017 by Ospedale San Raffaele
Sponsor:
Collaborator:
Fondazione Italiana Diabete Onlus
Information provided by (Responsible Party):
Piemonti Lorenzo, Ospedale San Raffaele
ClinicalTrials.gov Identifier:
NCT02505893
First received: July 21, 2015
Last updated: February 13, 2017
Last verified: February 2017
  Purpose
This is a prospective phase 2, single-arm, mono-center pilot study. It has been designed to investigate whether giving the combination therapy consisting of minimal islet transplantation (1500 EIQ/Kg body weight), Thymoglobulin® (ATG), Rapamune® (rapamycin) and Neulasta® (pegfilgastrim) to patients with Type 1 Diabetes (T1D) at onset is safe and secondarily, if it will preserve insulin production. It will involve 6 patients with new-onset T1D. Each patient will be involved in the study for a screening period and a post-islet transplantation study period of 52±2 weeks, to include 1 treatment cycles of 12 weeks, assessment during treatment and 5 follow-up visits scheduled at weeks 2±1 (14 days), 4±1 (month 1), 12±2 (month 3), 26±2 (month 6) and 52±2 (month 12).

Condition Intervention Phase
Diabetes Mellitus, Type 1
Biological: Human pancreatic islet
Drug: ATG
Drug: Pegylated G-CSF
Drug: Rapamycin
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Monocentric, Open-label Pilot Study to Assess the Safety and Efficacy of Minimal Islet Transplantation in Patients With New-onset Type 1 Diabetes

Resource links provided by NLM:


Further study details as provided by Ospedale San Raffaele:

Primary Outcome Measures:
  • plasma C-peptide AUC (mixed meal tolerance test [MMTT]) [ Time Frame: 52 weeks ]
    Mean change from baseline of stimulated plasma C-peptide AUC (mixed meal tolerance test [MMTT])

  • Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 52 weeks ]

Secondary Outcome Measures:
  • plasma C-peptide AUC (MMTT) [ Time Frame: 4,12, 26 weeks and 18, 24, 36, 48, 60 months ]
    Mean change from baseline in stimulated plasma C-peptide AUC (MMTT) at week 4, 12, 26 and month 18, 24, 36, 48, 60

  • stimulated plasma C-peptide [ Time Frame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months ]
    Maximum stimulated plasma C-peptide (the highest value at any time point during the MMTT after the mixed meal injection) at baseline, week 4, week 12, week 26 and week 52 and month 18, 24, 36, 48, 60

  • glucagon AUC (MMTT) [ Time Frame: 4,12, 26, 52 weeks ]
    Mean change from baseline in glucagon AUC (MMTT) at week 4, week 12, week 26 and week 52

  • HbA1c [ Time Frame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months ]
    Change from baseline in HbA1c at week 52 and HbA1c over time

  • daily insulin dose [ Time Frame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months ]
    Change from baseline in mean daily insulin dose for the 3 days preceding the visit at weeks 4, 12, 26, 52 and month 18, 24, 36, 48, 60. The mean daily insulin dose value will be calculated, in units of U/kg/day, as the mean of the values of amount of insulin used per day on each of the 3 consecutive days.

  • hypoglycaemic events [ Time Frame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months ]
    Number of hypoglycaemic events with confirmed self plasma glucose monitoring <3.1 mmol/L (<56 mg/dL) and/or requiring 3rd party intervention (i.e., severe, documented symptomatic and asymptomatic hypoglycaemic events) overall and in 3 monthly intervals

  • 72-hour Continuous Glucose Monitoring [ Time Frame: 26 and 52 weeks and 24, 36, 48, 60 months ]
    Time spent with a plasma glucose <3.9 mmol/L, between 3.9 and 10.0 mmol/L, and >10.0 mmol/L, respectively as performed by 72-hour CGM at baseline, week 26, week 52 and month 24, 36, 48, 60


Estimated Enrollment: 6
Study Start Date: April 2015
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treated
The investigational treatment will be islet transplant in the presence of induction with ATG/G-CSF and rapamycin treatment for one month. One thousand and five hundred (1,500) equivalent islet for Kg of body weight, isolated from a single brain-dead donor, will be infused into the patient's liver. ATG will be administered IV (central vein) at a total dose of 6 mg/kg up to day 6 post-transplant. Pegylated G-CSF (6 mg/dose) will be administered SC every 2 weeks for 6 doses (12 weeks) beginning after the last ATG infusion. Rapamycin will be administered orally at a starting dose of 0.2 mg/kg once a day, then targeted to blood trough level of 8-10 ng/mL and suspended one month after transplant.
Biological: Human pancreatic islet
One thousand and five hundred (1,500) equivalent islet for Kg of body weight, isolated from a single brain-dead donor, will be infused into the patient's liver.
Drug: ATG
ATG will be administered IV (central vein) at a total dose of 6 mg/kg up to day 6 post-transplant
Drug: Pegylated G-CSF
Pegylated G-CSF (6 mg/dose) will be administered SC every 2 weeks for 6 doses (12 weeks) beginning after the last ATG infusion
Drug: Rapamycin
Rapamycin will be administered orally at a starting dose of 0.2 mg/kg once a day, then targeted to blood trough level of 8-10 ng/mL and suspended one month after transplant.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to provide written informed consent
  • Mentally stable and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations
  • New-onset T1D (diagnosis of diabetes within 180 days prior to enrolment). Documentation of the diagnosis of T1DM (and not just insulin deficiency), including the date of diagnosis, must be obtained from the diagnosing physician.
  • Residual beta-cell function (fasting C-peptide >0.3 ng/mLwhen plasma glucose level is > 70 mg/dL and ≤ 200 mg/dL.
  • Positive for at least one of the following autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti-GAD) antibody to protein tyrosine phosphatase-like protein (anti-IA-2), zinc transporter autoantibodies; or an insulin autoantibody (IAA). Please note: A subject who is positive for IAA and negative for the other autoantibodies will not be eligible if the subject has been using insulin for a total of ≥7 days.
  • Currently requires insulin for T1DM treatment, or has required insulin therapy (for at least 7 days) for diabetes at some time between the date of diagnosis and the first dose of study drug. Note: subjects currently taking twice daily commercially available pre-mixed insulin will not be eligible.
  • MinimalHLA I A and B mismatch and at least one HLA DR match

Exclusion Criteria:

  • Body mass index (BMI) ≥ 32.0 kg/m2 or patient weight ≤50kg
  • Insulin requirement of >1.0 IU/kg/day
  • HbA1c >10%
  • Blood Pressure: SBP >160 mmHg or DBP >100 mmHg.
  • Chronic disease apart from diabetes, including type 2 diabetes
  • Moderate to severe renal impairment as per calculated creatinine clearance (CLcr) < 90 mL/min according to the Cockcroft-Gault formula (Cockcroft-Gault , 1976)
  • Presence or history of macroalbuminuria (>300mg/g creatinine).
  • Hepatic dysfunction defined by increased ALT/AST upper limit of normal (ULN) and increased total bilirubin > 3 mg/dL [>51.3 μmol/L]
  • Pregnant or breast feeding women. Unwillingness to use effective contraceptive measures up to 4 months after the end of study drug administration (females and males)
  • Active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB) as determined by a positive skin test or clinical presentation, or under treatment for suspected TB. Positive tests are acceptable only if associated with a history of previous vaccination in the absence of any sign of active infection. Positive tests are otherwise not acceptable, even in the absence of any active infection at the time of evaluation.
  • Negative screen for Epstein-Barr Virus (EBV) by IgG determination
  • Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study enrollment
  • Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin
  • Known active alcohol or substance abuse
  • Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia (<1,000/µL), neutropenia (<1,500/µL), or thrombocytopenia (platelets <100,000/µL). Participants with lymphopenia are allowed if the investigator determines there is no additional risk and obtains clearance from a hematologist
  • A history of Factor V deficiency
  • Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after transplantation (low-dose aspirin treatment is allowed) or patients with an international normalized ratio (INR) >1.5
  • Severe co-existing cardiac disease, characterized by any one of these conditions:

    • a) recent myocardial infarction (within past 6 months)
    • b) evidence of ischemia on functional cardiac exam within the last year
    • c) left ventricular ejection fraction <30%.
  • Symptomatic cholecystolithiasis.
  • Acute or chronic pancreatitis.
  • Symptomatic peptic ulcer disease.
  • Severe unremitting diarrhea, vomiting or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications
  • Hyperlipidemia despite medical therapy (fasting low-density lipoprotein [LDL] cholesterol >130 mg/dL, treated or untreated; and/or fasting triglycerides >200 mg/dL)
  • Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for the use of ≥ 5 mg prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only.
  • Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment
  • Use of any investigational agents within 4 weeks of enrollment.
  • Administration of live attenuated vaccine(s) within 2 months of enrollment.
  • Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial.
  • Treatment with any immunosuppressive regimen at the time of enrollment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02505893

Contacts
Contact: lorenzo Piemonti, MD 0226432706 ext 39 piemonti.lorenzo@hsr.it
Contact: Emauele Bosi, MD 0226432818 ext 39 emanuele.bosi@hsr.it

Locations
Italy
IRCCS San Raffaele Scientific Institute Recruiting
Milan, Italy, 20132
Contact: Lorenzo Piemonti, MD       piemonti.lorenzo@hsr.it   
Contact: Paola Maffi, MD       paola.maffi@hsr.it   
Sub-Investigator: Paola Maffi, MD         
Principal Investigator: Emanuele Bosi, MD         
Sub-Investigator: Andrea Bolla, MD         
Sponsors and Collaborators
Ospedale San Raffaele
Fondazione Italiana Diabete Onlus
Investigators
Principal Investigator: Lorenzo Piemonti, MD IRCCS Ospedale San Raffaele
Study Chair: Emanuele Bosi, MD IRCCS Ospedale San Raffaele
  More Information

Responsible Party: Piemonti Lorenzo, Deputy Director Diabetes Researh Institute, Ospedale San Raffaele
ClinicalTrials.gov Identifier: NCT02505893     History of Changes
Other Study ID Numbers: DRI-MITO 1/2014
Study First Received: July 21, 2015
Last Updated: February 13, 2017

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 21, 2017