Monotherapy With Rapamycin in Long-standing Type 1 Diabetes

NCT02803892 | Completed Phase 2

• 1 other identifier: DRI-2/2014 MONORAPA
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

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).

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• Change from Baseline insulin requirement

  week 4±1, week 12±2

• Change from Baseline fasting C-peptide

  week 4±1, week 12±2

• Change from Baseline HbA1c

  week 4±1, week 12±2

• Adverse Events (AEs) related to the immunosuppression

  week 4±1, week 12±2

• Adverse Events (AEs) and Serious Adverse Events (SAEs)

  week 4±1, week 12±2

Study Arms (3)

Group 1: Placebo

PLACEBO COMPARATOR

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; Drug: Placebo 2

Group 2: Rapamycin plus Placebo

EXPERIMENTAL

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; Drug: Vildagliptin

Group 3: Rapamycin plus Vildagliptin

EXPERIMENTAL

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; Drug: Vildagliptin

Interventions

rapamycin DRUG

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

Also known as: Rapamune®

Group 2: Rapamycin plus Placebo; Group 3: Rapamycin plus Vildagliptin

Vildagliptin DRUG

Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.

Also known as: GALVUS

Group 2: Rapamycin plus Placebo; Group 3: Rapamycin plus Vildagliptin

Placebo 1 DRUG

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

Group 1: Placebo

Placebo 2 DRUG

Placebo 2 will be administered BID starting from day 0. After 8 weeks of treatment patients will discontinue placebo 2

Group 1: Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Piemonti Lorenzo: lead
• Italian Diabetes Foundation: collaborator

Study Sites (1)

IRCCS San Raffaele Scientific Institute

Milan, 20132, Italy

Location

Related Publications (1)

• 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.

  PMID: 33124663 RESULT

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Sirolimus; Vildagliptin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Nitriles; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Lorenzo Piemonti, MD

  Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

• Emanuele Bosi, MD

  Ospedale San Raffaele

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director San Raffaele Diabetes Research Institute (SR-DRI)

Study Record Dates

• First Submitted: June 10, 2016
• First Posted: June 17, 2016
• Study Start: May 1, 2016
• Primary Completion: December 1, 2018
• Study Completion: March 1, 2019
• Last Updated: November 4, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

IT (1)