Monotherapy With Rapamycin in Long-standing Type 1 Diabetes (MONORAPA)

Piemonti Lorenzo

Status and phase: Completed; Phase 2

Conditions: Diabetes Mellitus, Type 1

Treatments: Drug: rapamycin; Drug: Placebo 2; Drug: Vildagliptin; Drug: Placebo 1

Study type: Interventional

Funder types: Other

Identifiers

NCT02803892

DRI-2/2014 MONORAPA

Details and patient eligibility

About

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).

Enrollment: 55 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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55 participants in 3 patient groups, including a placebo group

Group 1: Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo 2

Drug: Placebo 1

Group 2: Rapamycin plus Placebo

Experimental group

Description:

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

Treatment:

Drug: Vildagliptin

Drug: rapamycin

Group 3: Rapamycin plus Vildagliptin

Experimental group

Description:

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

Treatment:

Drug: Vildagliptin

Drug: rapamycin