Managing DIabetes Remission After Combined Therapy in EarLy Stage of DiabetEs (MIRACLE)

July 19, 2023 updated by: Riccardo Bonadonna, Azienda Ospedaliero-Universitaria di Parma

A Prospective, Randomized, Parallel-group, Adaptive Design Phase IIb/III, Multicenter Study, to Assess the Efficacy of Polychemotherapy for Inducing Remission of Newly Diagnosed Type 2 Diabetes.

Epidemiologic, social and economic burdens of type 2 diabetes mellitus (T2DM) keep rising worldwide. Implementation of T2DM preventive trategies is lagging behind. Metabolic surgery, very low calorie diet can induce T2DM remission, but so far for few patients. The investigators will assess the efficacy to cause T2DM remission (primary end point) and direct costs to the National Health System of a 4-month polychemotherapy (metformin+pioglitazone+sitagliptin+empagliflozin) regimen vs standard care in patients with newly diagnosed T2DM by an open label, pragmatic RCT. Mechanisms of action will be investigated in a sub-cohort by a prolonged OGTT plus dual tracer technique and modeling of beta cell function.

If proved efficacious in this proof-of-concept study and inducer of durable remission in the future, T2DM polychemotherapy will turn out to be a convenient, relatively unexpensive strategy to restrain prevalence of T2DM and its complications and to alleviate its personal, social and economic burden.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Hypothesis: at diagnosis of T2DM, a 4 month course of oral polychemotherapy (POLYCHEM), by engaging multiple glucose lowering mechanisms, results into euglycemia and, after suspension, in T2DM remission in a clinically significant higher number of patients when compared to standard diabetes care (SDC).

  • Diabetes remission: simultaneous nondiabetic values of fasting glucose, 2-hour glucose (after OGTT) and HbA1c for at least 12 months with no pharmacologic/surgical treatment of diabetes.
  • Complete remission: all values of fasting glucose, 2-hour glucose and HbA1c are within the limits of normal glucose regulation; otherwise, remission is partial.
  • Hyperglycemia remission as in diabetes remission, but duration<12 months.

Based on the "Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes" published on Diabetes Care 2021;44(10):2438-2444, remission should be defined as a return of HbA1c to <6.5% (<48 mmol/mol) that occurs spontaneously or following an intervention and that persists for at least 3 months in the absence of usual glucose-lowering pharmacotherapy.

A POLYCHEM (metformin, pioglitazone, sitagliptin and empagliflozin) will be used to improve:

  1. Insulin sensitivity of endogenous glucose output (EGO) and peripheral (muscle) glucose uptake (PGU);
  2. Beta cell function;
  3. GLP-1 and GIP bioavailability. To these effects, the direct glycosuric action of EMPA is added; EMPA effects on alpha cell and liver (increased glucagon secretion and EGO), may be, at least in part, counterbalanced by SITA and MET/PIO, respectively. Increased heart failure events with PIO may be, at least in part, counteracted by EMPA.

In many patients POLYCHEM should result in stable euglycemia, with negligible risk of hypoglycemia, and the number of patients in T2DM remission should be much higher than with MET+SU. The underpinning is that euglycemia reverses the detrimental effects of glucose toxicity and glucose regulation can be maintained in the nondiabetic range.

If the invesigators hypothesis is proved, POLYCHEM would be a convenient, simple and relatively unexpensive strategy to induce remission in a great number of patients with newly diagnosed T2DM. Novel, more efficacious goals of therapy could be introduced. Duration of remission is expected to delay the processes which result into the T2DM related risk of tissue damage. At the patient acceptance level, the trade off between the full T2DM burden (diabetes, its care and the risk of its complications) and the risk of T2DM relapse should favor the latter. At the society level, achieving a durable remission in a substantial number of these patients should attenuate, or even annull, the rises in prevalence, burden and tolls of "active" T2DM.

Patients with newly diagnosed (i.e. less than 6 months) T2DM will be recruited in the Diabetes Outpatient Clinics and will provide informed written consent before participation. After a screening visit (V0), patients will be randomized 1:1, with center stratification through web-based data collection (eCRF), to receive POLYCHEM or SDC with standard lifestyle intervention in both.

In both arms, patients will undergo planned visits at week 0 (V1), week 16 (V2), and week 28 (V3), after at least 3 days of drug washout. Patients will perform weekly a 6-point home blood glucose profile. Between week 17 and week 28, if a patient in hyperglycemia remission relapses, V3 will be anticipated (V3B), after which the patient will be treated as in SDC and will be re-evaluated at week 28 .

Visit procedures:

  • V0: assessment of patient eligibility , including medical history, physical examination, and lab exams, if needed.
  • V0S: between V0 and V1; signature of informed written consent and randomization.
  • V1, V2, V3 and V3B: assessment of anthropometry, ambulatory blood pressure and heart rate, WBC, fasting glucose, HbA1c, lipids, AST, ALT, creatinine, lipase, urine analysis, microalbuminuria, insulin, C-peptide, glucagon, GLP-1, GIP, quality of life (QoL), and, only in V1, blood for DNA collection (the last for post hoc studies).

POLYCHEM-ARM: After V1, patients will start POLYCHEM (MET titrated to 1000 mg b.i.d., PIO 15 mg b.i.d., SITA 100 mg q.d., EMPA 10 mg q.d.) for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others are transferred to SDC. Patients with MET intolerance will be treated with PIO+SITA+EMPA only.

SDC-ARM: After V1, patients will continue their SDC for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others continue SDC.

Study Type

Interventional

Enrollment (Estimated)

180

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Parma, Italy, 43126
        • Azienda Ospedaliero Universitaria di Parma

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

35 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion criteria:

  • Age 35-75 years;
  • HbA1c <= 10.0% (86 mmol/mol);
  • T2DM diagnosis (< 6 months)
  • BMI>=23 and <=40 kg/m2
  • Fasting C-peptide > 0.3 nmol/l;
  • GAD-antibody negative.

Exclusion criteria:

  • Diagnosis of type 1 diabetes;
  • History of cancer in the previous 5 years;
  • Multiple daily insulin treatment;
  • Acute cardiovascular event within the previous 6 months;
  • Chronic heart failure;
  • eGFR < 45 ml.min-1.1.73 m2 according to the MDRD formula;
  • Women of child bearing potential with no use of acceptable contraception;
  • Presence of diabetic retinopathy;
  • Contraindications to the use of any drug of POLYCHEM.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: POLYCHEM
Metformin (extended release), Pioglitazone, Sitagliptin and Empaglifozin.
Drug: Metformin-Sitagliptin-Empaglifozin-Pioglitazone
1000 mg metformin (extended release) b.i.d., pioglitazone 15 mg b.i.d., sitagliptin 100 mg q.d., empaglifozin 10 mg q.d..
Other Names:
  • POLYCHEM
Active Comparator: STANDARD CARE
Standard of care according to the local health service.
Drug: Standard of care
Usual medical care to treat diabetes.
Other Names:
  • SDC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assess the T2DM remission rate in patients with newly diagnosed T2DM treated with either POLYCHEM or with SDC for 16 weeks.
Time Frame: 12 weeks after the end of treatment
Remission was defined as HbA1c <6.5% or 48mmol/mol for at least 12 weeks without pharmacologic or surgical treatment for diabetes.
12 weeks after the end of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assess the proportion of complete T2DM remission rate in the 2 groups
Time Frame: 12 weeks after the end of treatment
Normal measures of glucose metabolism (fasting glucose and HbA1c in normal range), for at least 12weeks without pharmacologic or surgical treatment for diabetes.
12 weeks after the end of treatment
Monitor the quality of life EQ-5D-DL
Time Frame: 0, 16, 28 weeks
Will be monitored through EQ-5D-DL questionnaires.
0, 16, 28 weeks
Monitor the quality of life ADDQOL
Time Frame: 0, 16, 28 weeks
QoL will be monitored through ADDQOL questionnaires.
0, 16, 28 weeks
Monitor the costs of National Health System service utilization
Time Frame: 0, 16, 28 weeks
All accesses to the National Healthcare System resources by each patient (visits, treatments, supplies, hospital admissions, etc.) will be retrieved from the Regional Health Registries and recorded. Costs will be assessed from a public purchaser perspective. For this reason all costs will refer to the reimbursement provided to the health facilities by the national health system.
0, 16, 28 weeks
Quantify the effects of either POLYCHEM or SDC on the main determinants of glucose regulation
Time Frame: 0, 16, 28 weeks
In all patients C-peptide will be used to compute static surrogate indexes of insulin sensitivity and beta cell function.
0, 16, 28 weeks
Quantify the effects of either POLYCHEM or SDC on the main determinants of glucose regulation
Time Frame: 0, 16, 28 weeks
In all patients insulin values will be used to compute static surrogate indexes of insulin sensitivity and beta cell function.
0, 16, 28 weeks
Quantify the effects of either POLYCHEM or SDC on the main determinants of glucose regulation
Time Frame: 0, 16, 28 weeks
Glucagon values will provide indexes of alpha cell function and of gut K- and L-cell function. Their role in predicting and/or explaining T2DM remission and/or relapse will be assessed.
0, 16, 28 weeks
Quantify the effects of either POLYCHEM or SDC on the main determinants of glucose regulation
Time Frame: 0, 16, 28 weeks
GLP-1 values will provide indexes of alpha cell function and of gut K- and L-cell function. Their role in predicting and/or explaining T2DM remission and/or relapse will be assessed.
0, 16, 28 weeks
Quantify the effects of either POLYCHEM or SDC on the main determinants of glucose regulation
Time Frame: 0, 16, 28 weeks
GIP values will provide indexes of alpha cell function and of gut K- and L-cell function. Their role in predicting and/or explaining T2DM remission and/or relapse will be assessed.
0, 16, 28 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliero-Universitaria di Parma

Investigators

  • Principal Investigator: Riccardo Bonadonna, MD, Azienda Ospedaliero-Universitaria di Parma

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2020

Primary Completion (Estimated)

March 2, 2024

Study Completion (Estimated)

May 31, 2024

Study Registration Dates

First Submitted

October 15, 2019

First Submitted That Met QC Criteria

February 12, 2020

First Posted (Actual)

February 17, 2020

Study Record Updates

Last Update Posted (Actual)

July 20, 2023

Last Update Submitted That Met QC Criteria

July 19, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018-833-12

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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