Monotherapy With Rapamycin in Long-standing Type 1 Diabetes

Study 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).

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

Conditions
-----------------
Diabetes Mellitus, Type 1

Intervention / Treatment
-----------------
* Drug: rapamycin
* Drug: Vildagliptin
* Drug: Placebo 1
* Drug: Placebo 2


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1: Placebo<br>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 | Drug: Placebo 1<br>* 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<br>Drug: Placebo 2<br>* Placebo 2 will be administered BID starting from day 0. After 8 weeks of treatment patients will discontinue placebo 2<br>|
| Experimental: Group 2: Rapamycin plus Placebo<br>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 | Drug: rapamycin<br>* 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<br>* Other names: Rapamune®;Drug: Vildagliptin<br>* Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.<br>* Other names: GALVUS;|
| Experimental: Group 3: Rapamycin plus Vildagliptin<br>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 | Drug: rapamycin<br>* 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<br>* Other names: Rapamune®;Drug: Vildagliptin<br>* Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.<br>* Other names: GALVUS;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline C-peptide response in the MMTT | the proportion of participants with a positive response to the MMTT defined as C-peptide at 90 min >0.6 ng/ml. | week 4±1, week 12±2 | 
| Change from Baseline C-peptide after the MMTT | change in the area under the curve of C-peptide after the MMTT vs baseline | week 4±1, week 12±2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline insulin requirement | change in insulin requirement vs baseline | week 4±1, week 12±2 | 
| Change from Baseline fasting C-peptide | change in fasting C-peptide vs baseline | week 4±1, week 12±2 | 
| Change from Baseline HbA1c | change in HbA1c vs baseline | week 4±1, week 12±2 | 
| Adverse Events (AEs) related to the immunosuppression | the incidence and severity of Adverse Events (AEs) related to the immunosuppressive treatment | week 4±1, week 12±2 | 
| Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | week 4±1, week 12±2 |