Monotherapy With Rapamycin in Long-standing Type 1 Diabetes

Diabetes Mellitus, Type 1 Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02803892
• Other study ID #: DRI-2/2014 MONORAPA
• Status: Completed
• Phase: Phase 2
• Start date: May 2016
• Est. completion date: March 2019

Study information

• Verified date: November 2020
• Source: Ospedale San Raffaele
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: March 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

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
• Vildagliptin
Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.
• 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
• Placebo 2
Placebo 2 will be administered BID starting from day 0. After 8 weeks of treatment patients will discontinue placebo 2

Locations

Country	Name	City	State
Italy	IRCCS San Raffaele Scientific Institute	Milan

Sponsors (2)

Lead Sponsor	Collaborator
Piemonti Lorenzo	Italian Diabetes Foundation

Country where clinical trial is conducted

Italy, 

References & 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 ß Cell Function in Long Standing Typ — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Change from Baseline insulin requirement	change in insulin requirement vs baseline	week 4±1, week 12±2
Secondary	Change from Baseline fasting C-peptide	change in fasting C-peptide vs baseline	week 4±1, week 12±2
Secondary	Change from Baseline HbA1c	change in HbA1c vs baseline	week 4±1, week 12±2
Secondary	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
Secondary	Adverse Events (AEs) and Serious Adverse Events (SAEs)	Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)	week 4±1, week 12±2