A Monocentric, Open-label Pilot Study to Assess the Safety and Efficacy of Minimal Islet Transplantation in Patients With New-onset Type 1 Diabetes
Overview
- Phase
- Phase 2
- Intervention
- Human pancreatic islet
- Conditions
- Diabetes Mellitus, Type 1
- Sponsor
- Ospedale San Raffaele
- Enrollment
- 6
- Locations
- 1
- Primary Endpoint
- plasma C-peptide AUC (mixed meal tolerance test [MMTT])
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
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).
Investigators
Lorenzo Piemonti
Deputy Director Diabetes Researh Institute
Ospedale San Raffaele
Eligibility 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.
Arms & Interventions
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.
Intervention: Human pancreatic islet
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.
Intervention: ATG
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.
Intervention: Pegylated G-CSF
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.
Intervention: Rapamycin
Outcomes
Primary Outcomes
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 Outcomes
- stimulated plasma C-peptide(4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months)
- glucagon AUC (MMTT)(4,12, 26, 52 weeks)
- daily insulin dose(4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months)
- HbA1c(4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months)
- plasma C-peptide AUC (MMTT)(4,12, 26 weeks and 18, 24, 36, 48, 60 months)
- hypoglycaemic events(4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months)
- 72-hour Continuous Glucose Monitoring(26 and 52 weeks and 24, 36, 48, 60 months)