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

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

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).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Placebo 1; Drug: Placebo 2; Drug: rapamycin; Drug: Vildagliptin

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • IRCCS San Raffaele Scientific Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 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	Drug: Placebo 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; Drug: Placebo 2; Placebo 2 will be administered BID starting from day 0. After 8 weeks of treatment patients will discontinue placebo 2
Experimental: 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	Drug: rapamycin; 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; Other Names: Rapamune®; Drug: Vildagliptin; Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.; Other Names: GALVUS
Experimental: 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	Drug: rapamycin; 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; Other Names: Rapamune®; Drug: Vildagliptin; Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.; 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

Collaborators and Investigators

• Sponsor: Piemonti Lorenzo
• Collaborators: Italian Diabetes Foundation
• Investigators: Principal Investigator: Lorenzo Piemonti, MD, Ospedale San Raffaele; Study Chair: Emanuele Bosi, MD, Ospedale San Raffaele

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): March 1, 2019

Study Registration Dates

• First Submitted: June 10, 2016
• First Submitted That Met QC Criteria: June 14, 2016
• First Posted (Estimate): June 17, 2016

Study Record Updates

• Last Update Posted (Actual): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protease Inhibitors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Dipeptidyl-Peptidase IV Inhibitors; Sirolimus; Vildagliptin
• Other Study ID Numbers: DRI-2/2014 MONORAPA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL