Diabetes Mellitus, Type 1
Conditions
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).
Interventions
DRUGrapamycin
Rapamycin will be administered at an initial dose 0.2 mg/kg on day 0, followed by 0.1 mg/kg/die. The daily dose will be adjusted to the whole blood 24-hr trough to target, as tolerated, 8-10 ng/mL
DRUGVildagliptin
Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.
DRUGPlacebo 1
Placebo 1 will be titrated according to a random schedule alternating plausible doses of placebo. After 4 weeks of treatment patients will discontinue placebo 1
DRUGPlacebo 2
Placebo 2 will be administered BID starting from day 0. After 8 weeks of treatment patients will discontinue placebo 2
Sponsors
Italian Diabetes Foundation
Piemonti Lorenzo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline C-peptide response in the MMTT | 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 | week 4±1, week 12±2 | change in the area under the curve of C-peptide after the MMTT vs baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline HbA1c | week 4±1, week 12±2 | change in HbA1c vs baseline |
| Change from Baseline insulin requirement | week 4±1, week 12±2 | change in insulin requirement vs baseline |
| Adverse Events (AEs) and Serious Adverse Events (SAEs) | week 4±1, week 12±2 | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) |
| Adverse Events (AEs) related to the immunosuppression | week 4±1, week 12±2 | the incidence and severity of Adverse Events (AEs) related to the immunosuppressive treatment |
| Change from Baseline fasting C-peptide | week 4±1, week 12±2 | change in fasting C-peptide vs baseline |
Countries
Italy
Outcome results
None listed