Monotherapy With Rapamycin in Long-standing Type 1 Diabetes

NCT ID: NCT02803892

Last Updated: 2020-11-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-05-31
• Study Completion Date: 2019-03-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

Group Type: PLACEBO_COMPARATOR

Placebo 1

Intervention Type: 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

Placebo 2

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

rapamycin

Intervention Type: 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

Vildagliptin

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

rapamycin

Intervention Type: 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

Vildagliptin

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

Vildagliptin

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

Intervention Type: 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

Intervention Type: DRUG

Placebo 2

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

Intervention Type: DRUG

Other Intervention Names

Rapamune®; GALVUS

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Italian Diabetes Foundation

OTHER

Sponsor Role: collaborator

Piemonti Lorenzo

OTHER

Sponsor Role: lead

Responsible Party

Piemonti Lorenzo

Director San Raffaele Diabetes Research Institute (SR-DRI)

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Lorenzo Piemonti, MD

Role: PRINCIPAL_INVESTIGATOR

Ospedale San Raffaele

Emanuele Bosi, MD

Role: STUDY_CHAIR

Ospedale San Raffaele

Locations

IRCCS San Raffaele Scientific Institute

Milan, , Italy

Countries

Italy

References

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.

Reference Type: RESULT

PMID: 33124663 (View on PubMed)

Other Identifiers

DRI-2/2014 MONORAPA

Identifier Type: -

Identifier Source: org_study_id