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.
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Enrollment
- 108
- Locations
- 1
- Primary Endpoint
- Assess the T2DM remission rate in patients with newly diagnosed T2DM treated with either POLYCHEM or with SDC for 16 weeks.
Study Overview
Brief Summary
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.
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:
- Insulin sensitivity of endogenous glucose output (EGO) and peripheral (muscle) glucose uptake (PGU);
- Beta cell function;
- 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 35 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
POLYCHEM
Metformin (extended release), Pioglitazone, Sitagliptin and Empaglifozin.
Intervention: Metformin-Sitagliptin-Empaglifozin-Pioglitazone (Drug)
STANDARD CARE
Standard of care according to the local health service.
Intervention: Standard of care (Drug)
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- Assess the proportion of complete T2DM remission rate in the 2 groups(12 weeks after the end of treatment)
- Monitor the costs of National Health System service utilization(0, 16, 28 weeks)
- Monitor the quality of life EQ-5D-DL(0, 16, 28 weeks)
- Monitor the quality of life ADDQOL(0, 16, 28 weeks)
- Quantify the effects of either POLYCHEM or SDC on the main determinants of glucose regulation(0, 16, 28 weeks)
Investigators
Riccardo Bonadonna
Director of Endocrinology Unit
Azienda Ospedaliero-Universitaria di Parma