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
Overview
- Phase
- Phase 2
- Intervention
- Placebo 1
- Conditions
- Diabetes Mellitus, Type 1
- Sponsor
- Piemonti Lorenzo
- Enrollment
- 55
- Locations
- 1
- Primary Endpoint
- Change from Baseline C-peptide response in the MMTT
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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).
Investigators
Piemonti Lorenzo
Director San Raffaele Diabetes Research Institute (SR-DRI)
Ospedale San Raffaele
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
Arms & Interventions
Group 1: Placebo
Eligible participants will be randomized to one of three treatment arms. In this arm patients will received placebo x 2 placebo (Group 1) After 4 weeks of treatment, patients will discontinue relevant placebo treatment, but continue the second placebo for a further 8 weeks
Intervention: Placebo 1
Group 1: Placebo
Eligible participants will be randomized to one of three treatment arms. In this arm patients will received placebo x 2 placebo (Group 1) After 4 weeks of treatment, patients will discontinue relevant placebo treatment, but continue the second placebo for a further 8 weeks
Intervention: Placebo 2
Group 2: Rapamycin plus Placebo
Eligible participants will be randomized to one of three treatment arms. In this arm patients will received rapamycin plus placebo. After 4 weeks of treatment, patients will discontinue rapamycin, but continue the second placebo for a further 8 weeks
Intervention: rapamycin
Group 2: Rapamycin plus Placebo
Eligible participants will be randomized to one of three treatment arms. In this arm patients will received rapamycin plus placebo. After 4 weeks of treatment, patients will discontinue rapamycin, but continue the second placebo for a further 8 weeks
Intervention: Vildagliptin
Group 3: Rapamycin plus Vildagliptin
Eligible participants will be randomized to one of three treatment arms. In this arm patients will received rapamycin plus vildagliptin. After 4 weeks of treatment, patients will discontinue rapamycin , but continue Vildagliptin o for a further 8 weeks
Intervention: rapamycin
Group 3: Rapamycin plus Vildagliptin
Eligible participants will be randomized to one of three treatment arms. In this arm patients will received rapamycin plus vildagliptin. After 4 weeks of treatment, patients will discontinue rapamycin , but continue Vildagliptin o for a further 8 weeks
Intervention: Vildagliptin
Outcomes
Primary Outcomes
Change from Baseline C-peptide response in the MMTT
Time Frame: week 4±1, week 12±2
the proportion of participants with a positive response to the MMTT defined as C-peptide at 90 min \>0.6 ng/ml.
Change from Baseline C-peptide after the MMTT
Time Frame: week 4±1, week 12±2
change in the area under the curve of C-peptide after the MMTT vs baseline
Secondary Outcomes
- Change from Baseline HbA1c(week 4±1, week 12±2)
- Adverse Events (AEs) related to the immunosuppression(week 4±1, week 12±2)
- Change from Baseline insulin requirement(week 4±1, week 12±2)
- Change from Baseline fasting C-peptide(week 4±1, week 12±2)
- Adverse Events (AEs) and Serious Adverse Events (SAEs)(week 4±1, week 12±2)