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

Study Description

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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).

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Drug: rapamycin; Drug: Vildagliptin; Drug: Placebo 1; Drug: Placebo 2	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Care Provider)
Primary Purpose:	Treatment
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 Start Date :	May 2016
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	March 2019

Arms and Interventions

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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 Name: Rapamune®; Drug: Vildagliptin; Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.; Other Name: 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 Name: Rapamune®; Drug: Vildagliptin; Vildagliptin will be administered at a dose of 50 mg x2/die starting from day 0.; Other Name: GALVUS

Outcome Measures

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Primary Outcome Measures :

1. Change from Baseline C-peptide response in the MMTT [ Time Frame: week 4±1, week 12±2 ]
   the proportion of participants with a positive response to the MMTT defined as C-peptide at 90 min >0.6 ng/ml.
2. Change from Baseline C-peptide after the MMTT [ Time Frame: week 4±1, week 12±2 ]
   change in the area under the curve of C-peptide after the MMTT vs baseline

Secondary Outcome Measures :

1. Change from Baseline insulin requirement [ Time Frame: week 4±1, week 12±2 ]
   change in insulin requirement vs baseline
2. Change from Baseline fasting C-peptide [ Time Frame: week 4±1, week 12±2 ]
   change in fasting C-peptide vs baseline
3. Change from Baseline HbA1c [ Time Frame: week 4±1, week 12±2 ]
   change in HbA1c vs baseline
4. Adverse Events (AEs) related to the immunosuppression [ Time Frame: week 4±1, week 12±2 ]
   the incidence and severity of Adverse Events (AEs) related to the immunosuppressive treatment
5. Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: week 4±1, week 12±2 ]
   Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Contacts

Contact: Lorenzo Piemonti, MD	0226432706 ext +39	piemonti.lorenzo@hsr.it
Contact: Andrea Bolla, MD	0226432822 ext +39	andrea.bolla@hsr.it

Locations

Italy
IRCCS San Raffaele Scientific Institute	Recruiting
Milan, Italy, 20132
Contact: Lorenzo Piemonti, MD piemonti.lorenzo@hsr.it
Contact: Andrea Bolla, MD andrea.bolla@hsr.it
Principal Investigator: Andrea Bolla, MD
Principal Investigator: Lorenzo Piemonti, MD
Principal Investigator: Emanuele Bosi, MD

Sponsors and Collaborators

Piemonti Lorenzo

Italian Diabetes Foundation

Investigators

Principal Investigator:	Lorenzo Piemonti, MD	Ospedale San Raffaele
Study Chair:	Emanuele Bosi, MD	Ospedale San Raffaele

More Information

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Responsible Party:	Piemonti Lorenzo, Deputy director San Raffaele Diabetes Research Institute (SR-DRI), Ospedale San Raffaele
ClinicalTrials.gov Identifier:	NCT02803892 History of Changes
Other Study ID Numbers:	DRI-2/2014 MONORAPA
First Posted:	June 17, 2016
Last Update Posted:	February 8, 2018
Last Verified:	February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Sirolimus; Everolimus; Vildagliptin; Dipeptidyl-Peptidase IV Inhibitors; Anti-Bacterial Agents	Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents