Monotherapy With Rapamycin in Long-standing Type 1 Diabetes
Monotherapy With Rapamycin in Long-standing Type 1 Diabetes
This study is a phase 2, single-center, prospective, randomized, double-blind,
 placebo-controlled, 3-arm parallel group (1:1:1) intervention trial to determine the efficacy
 of 4 weeks rapamycin treatment and 4 weeks rapamycin treatment plus 3 months vildagliptin
 treatment versus placebo in increasing endogenous insulin production and correcting glycemic
 lability. It will involve 60 patients with long standing type 1 diabetes (T1D). Patients will
 receive for one month placebo (Group 1), rapamycin plus placebo (Group 2), or rapamycin plus
 Vildagliptin (Group 3). Rapamycin will be administered at an initial dose 0.2 mg/kg orally on
 day 0 followed by 0.1 mg/kg/die (target trough levels: 8-10 ng/ml). Vildagliptin will be
 administered at a dose of 50 mg x2/die starting from day 0. After 4 weeks of treatment
 (period A), patients will discontinue rapamycin or relevant placebo treatment, but continue
 Vildagliptin or placebo for a further 8 weeks and be monitored over this period (period B).
Inclusion Criteria:

 -  Male or female aged >18 years, inclusive

 -  Clinical history compatible with T1D with onset of disease at < 40 years of age,
 insulin dependence for ≥ 5 years at the time of enrolment

 -  C-peptide concentrations under the threshold of preserved beta cell function: fasting
 C peptide <0.23 ng/ml

 -  Detectable fasting proinsulin concentrations (>0.5 pmol/l)

 -  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

 Exclusion Criteria:

 -  Body mass index (BMI) >30 kg/m2 or patient with body weight ≤40kg;

 -  Insulin requirement >1.0 IU/kg/day or <10 U/day;

 -  HbA1c >11% (normal value: 3.5-6.0%) at the time of enrolment

 -  estimated glomerular filtration rate <60 mL/min/1.73m2 calculated using the subject's
 measured serum creatinine and the Modification of Diet in Renal Disease [MDRD] study
 estimation formula)

 -  Presence or history of macroalbuminuria (>300mg/g creatinine)

 -  For female subjects: positive pregnancy test, presently breast-feeding, or
 unwillingness to use effective contraceptive measures for the duration of the study
 and 4 months after discontinuation of treatment

 -  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

 -  Any history of malignancy except for completely resected squamous or basal cell
 carcinoma of the skin

 -  Lymphopenia (<1,000/μL), neutropenia (<1,500/μL), or thrombocytopenia (platelets
 <100,000/μL).

 -  Severe unremitting diarrhea, vomiting or other gastrointestinal disorders potentially
 interfering with the ability to absorb oral medications

 -  Any medical condition that will interfere with safe participation in the trial;

 -  Any immunosuppressive treatment at the time of enrollment.

 -  Allergy to active ingredients or to any of excipients