Minimal Islet Transplant at Diabetes Onset

Study Overview
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Brief Summary
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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).

Official Title
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A Monocentric, Open-label Pilot Study to Assess the Safety and Efficacy of Minimal Islet Transplantation in Patients With New-onset Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Biological: Human pancreatic islet
* Drug: ATG
* Drug: Pegylated G-CSF
* Drug: Rapamycin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treated<br>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<br>* 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.<br>Drug: ATG<br>* ATG will be administered IV (central vein) at a total dose of 6 mg/kg up to day 6 post-transplant<br>Drug: Pegylated G-CSF<br>* Pegylated G-CSF (6 mg/dose) will be administered SC every 2 weeks for 6 doses (12 weeks) beginning after the last ATG infusion<br>Drug: Rapamycin<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma C-peptide AUC (mixed meal tolerance test [MMTT]) | Mean change from baseline of stimulated plasma C-peptide AUC (mixed meal tolerance test [MMTT]) | 52 weeks | 
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma C-peptide AUC (MMTT) | Mean change from baseline in stimulated plasma C-peptide AUC (MMTT) at week 4, 12, 26 and month 18, 24, 36, 48, 60 | 4,12, 26 weeks and 18, 24, 36, 48, 60 months | 
| stimulated plasma C-peptide | 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 | 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months | 
| glucagon AUC (MMTT) | Mean change from baseline in glucagon AUC (MMTT) at week 4, week 12, week 26 and week 52 | 4,12, 26, 52 weeks | 
| HbA1c | Change from baseline in HbA1c at week 52 and HbA1c over time | 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months | 
| daily insulin dose | 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. | 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months | 
| hypoglycaemic events | 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 | 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months | 
| 72-hour Continuous Glucose Monitoring | 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 | 26 and 52 weeks and 24, 36, 48, 60 months |