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

Primary Purpose

Diabetes Mellitus, Type 1

Status

Completed

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

rapamycin

Vildagliptin

Placebo 1

Placebo 2

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

IRCCS San Raffaele Scientific Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Arm Label

Group 1: Placebo

Group 2: Rapamycin plus Placebo

Group 3: Rapamycin plus Vildagliptin

Arm 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

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

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

Outcomes

Primary Outcome Measures

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.

Change from Baseline C-peptide after the MMTT

change in the area under the curve of C-peptide after the MMTT vs baseline

Secondary Outcome Measures

Change from Baseline insulin requirement

change in insulin requirement vs baseline

Change from Baseline fasting C-peptide

change in fasting C-peptide vs baseline

Change from Baseline HbA1c

change in HbA1c vs baseline

Adverse Events (AEs) related to the immunosuppression

the incidence and severity of Adverse Events (AEs) related to the immunosuppressive treatment

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

Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Full Information

NCT ID

NCT02803892

First Posted

June 10, 2016

Last Updated

November 2, 2020

Sponsor

Piemonti Lorenzo

Collaborators

Italian Diabetes Foundation

1. Study Identification

Unique Protocol Identification Number

NCT02803892

Brief Title

Monotherapy With Rapamycin in Long-standing Type 1 Diabetes

Acronym

MONORAPA

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Completed

Study Start Date

May 2016 (Actual)

Primary Completion Date

December 2018 (Actual)

Study Completion Date

March 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Piemonti Lorenzo

Collaborators

Italian Diabetes Foundation

4. Oversight

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type 1

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare Provider

Allocation

Randomized

Enrollment

55 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1: Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

Group 2: Rapamycin plus Placebo

Arm Type

Experimental

Arm Description

Arm Title

Group 3: Rapamycin plus Vildagliptin

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

rapamycin

Other Intervention Name(s)

Rapamune®

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Vildagliptin

Other Intervention Name(s)

GALVUS

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo 1

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo 2

Intervention Description

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

Primary Outcome Measure Information:

Title

Change from Baseline C-peptide response in the MMTT

Description

the proportion of participants with a positive response to the MMTT defined as C-peptide at 90 min >0.6 ng/ml.

Time Frame

week 4±1, week 12±2

Title

Change from Baseline C-peptide after the MMTT

Description

change in the area under the curve of C-peptide after the MMTT vs baseline

Time Frame

week 4±1, week 12±2

Secondary Outcome Measure Information:

Title

Change from Baseline insulin requirement

Description

change in insulin requirement vs baseline

Time Frame

week 4±1, week 12±2

Title

Change from Baseline fasting C-peptide

Description

change in fasting C-peptide vs baseline

Time Frame

week 4±1, week 12±2

Title

Change from Baseline HbA1c

Description

change in HbA1c vs baseline

Time Frame

week 4±1, week 12±2

Title

Adverse Events (AEs) related to the immunosuppression

Description

the incidence and severity of Adverse Events (AEs) related to the immunosuppressive treatment

Time Frame

week 4±1, week 12±2

Title

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

Description

Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame

week 4±1, week 12±2

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lorenzo Piemonti, MD

Organizational Affiliation

Ospedale San Raffaele

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Emanuele Bosi, MD

Organizational Affiliation

Ospedale San Raffaele

Official's Role

Study Chair

Facility Information:

Facility Name

IRCCS San Raffaele Scientific Institute

City

Milan

ZIP/Postal Code

20132

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

Yes

Citations:

PubMed Identifier

33124663

Citation

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.

Results Reference

result

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Monotherapy With Rapamycin in Long-standing Type 1 Diabetes

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