Clinical trial NCT02803892: Monotherapy With Rapamycin in Long-standing Type 1 Diabetes
Official title: Evaluation of the Efficacy of Rapamycin and a Dipeptidyl Peptidase-4 Inhibitor (Vildagliptin) in Improving Beta Cell Function in Type 1 Diabetes of Long Duration, a Perspective Randomized Study
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: 2016-06-17
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Change from Baseline C-peptide response in the MMTT
timeFrame: week 4±1, week 12±2
measure: Change from Baseline C-peptide after the MMTT
timeFrame: week 4±1, week 12±2
Secondary outcomes:
measure: Change from Baseline insulin requirement
timeFrame: week 4±1, week 12±2
measure: Change from Baseline fasting C-peptide
timeFrame: week 4±1, week 12±2
measure: Change from Baseline HbA1c
timeFrame: week 4±1, week 12±2
measure: Adverse Events (AEs) related to the immunosuppression
timeFrame: week 4±1, week 12±2
measure: Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: week 4±1, week 12±2
Other outcomes:
Locations:
city: Milan
country: Italy
facility: IRCCS San Raffaele Scientific Institute
Study officials:
affiliation: Ospedale San Raffaele
name: Lorenzo Piemonti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale San Raffaele
name: Emanuele Bosi, MD
role: STUDY_CHAIR
References:
citation: Bolla AM, Gandolfi A, Borgonovo E, Laurenzi A, Caretto A, Molinari C, Catalano RS, Bianconi E, Monti P, Sordi V, Pellegrini S, Lampasona V, Costa S, Scavini M, Bosi E, Piemonti L. Rapamycin Plus Vildagliptin to Recover beta-Cell Function in Long-Standing Type 1 Diabetes: A Double-Blind, Randomized Trial. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e507-e519. doi: 10.1210/clinem/dgaa791.