Minimal Islet Transplant at Diabetes Onset

NCT02505893 | Completed Phase 2

• 1 other identifier: DRI-MITO 1/2014
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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).

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• plasma C-peptide AUC (MMTT)

  4,12, 26 weeks and 18, 24, 36, 48, 60 months

• stimulated plasma C-peptide

  4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months

• glucagon AUC (MMTT)

  4,12, 26, 52 weeks

• HbA1c

  4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months

• daily insulin dose

  4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months

Study Arms (1)

Treated

EXPERIMENTAL

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; Drug: ATG; Drug: Pegylated G-CSF; Drug: Rapamycin

Interventions

Human pancreatic islet BIOLOGICAL

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.

Treated

ATG DRUG

ATG will be administered IV (central vein) at a total dose of 6 mg/kg up to day 6 post-transplant

Treated

Pegylated G-CSF DRUG

Pegylated G-CSF (6 mg/dose) will be administered SC every 2 weeks for 6 doses (12 weeks) beginning after the last ATG infusion

Treated

Rapamycin DRUG

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.

Treated

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ospedale San Raffaele: lead
• Italian Diabetes Foundation: collaborator

Study Sites (1)

IRCCS San Raffaele Scientific Institute

Milan, 20132, Italy

Location

Related Publications (1)

• Piemonti L, Bolla AM, Caretto A, Melzi R, Mercalli A, Sordi V, Monti P, Magistretti P, Lampasona V, Marzinotto I, Maffi P, Ramondetta M, Cagni N, Pedone E, Catarinella D, Cardillo M, Caldara R, Bosi E. Induction of immune education in type 1 diabetes through controlled allogeneic islet rejection at onset: a monocentric open-label pilot study. EClinicalMedicine. 2025 Dec 4;90:103685. doi: 10.1016/j.eclinm.2025.103685. eCollection 2025 Dec.

  PMID: 41438972 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Lorenzo Piemonti, MD

  IRCCS Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

• Emanuele Bosi, MD

  IRCCS Ospedale San Raffaele

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Deputy Director Diabetes Researh Institute

Study Record Dates

• First Submitted: July 21, 2015
• First Posted: July 22, 2015
• Study Start: April 1, 2015
• Primary Completion: May 1, 2018
• Study Completion: December 1, 2023
• Last Updated: February 22, 2024

Record last verified: 2024-02

Locations

IT (1)