Clinical trial NCT02505893: Minimal Islet Transplant at Diabetes Onset
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Lead sponsor: Ospedale San Raffaele
Sponsor class: OTHER
Collaborators: name: Italian Diabetes Foundation
First posted: 2015-07-22
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


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.
* 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.

Primary outcomes:
measure: plasma C-peptide AUC (mixed meal tolerance test [MMTT])
timeFrame: 52 weeks
measure: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 52 weeks
Secondary outcomes:
measure: plasma C-peptide AUC (MMTT)
timeFrame: 4,12, 26 weeks and 18, 24, 36, 48, 60 months
measure: stimulated plasma C-peptide
timeFrame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months
measure: glucagon AUC (MMTT)
timeFrame: 4,12, 26, 52 weeks
measure: HbA1c
timeFrame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months
measure: daily insulin dose
timeFrame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months
measure: hypoglycaemic events
timeFrame: 4,12, 26 weeks and 12, 18, 24, 36, 48, 60 months
measure: 72-hour Continuous Glucose Monitoring
timeFrame: 26 and 52 weeks and 24, 36, 48, 60 months
Other outcomes:
Locations:
city: Milan
country: Italy
facility: IRCCS San Raffaele Scientific Institute
Study officials:
affiliation: IRCCS Ospedale San Raffaele
name: Lorenzo Piemonti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCCS Ospedale San Raffaele
name: Emanuele Bosi, MD
role: STUDY_CHAIR
References: