Empagliflozin and ACEi- Effects on Hyperfiltration: BETWEEN Study

A Double-blind, Placebo Controlled, Cross-over Renal Mechanistic Trial to Assess the Effect of Adding Empagliflozin Versus Placebo on Renal Hyperfiltration on a Background of the Angiotensin Converting Enzyme Inhibitor (ACEi) Ramipril: BETWEEN Study

This is a randomized, double-blind, double-dummy, placebo-controlled, cross over design trial with empagliflozin compared to placebo that is added to open-label ramipril.

Study Overview

• Status: Completed
• Conditions: Obesity; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Empagliflozin; Drug: Placebo (matching empagliflozin); Drug: ramipril

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Signed and dated written informed consent.
• Male or female patients diagnosed with type 1 diabetes (T1D) at least 6 months prior to informed consent or type 2 diabetes (T2D) or non-diabetic obese patients.
• T1D patients must use and be willing of and be willing to continue throughout the duration of the trial either:
• multiple daily injections of insulin OR
• continuous sub-cutaneous insulin infusion of any insulin type, with at least 3 months experience
• For patients with T1D or T2D,HbA1c of 6.5 - 11%
• Age at least 18 years of age
• Body mass index of >=18.5 kg/m^2
• Estimated glomerular filtration rate greater than or equal to 60 ml/min/1.73m2
• Blood pressure greater than 90 /60 mmHg and less than or equal to 140 / 90 mmHg
• Use of a highly effective method of contraception.
• Further inclusion criteria apply

Exclusion criteria:

• For patients with T1D, treatment with an antihyperglycaemic agent within 3 months prior to visit 1
• occurrence of severe hypoglycaemia within 3 months prior to visit 1
• hypoglycaemic unawareness within 3 months prior to visit 1
• occurrence of diabetic ketoacidosis within 3 months of visit 1 and until visit 3 Further exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sequence A; Empagliflozin followed by a wash-out followed by empagliflozin matching placebo on a background of open label ramipril.	Drug: Empagliflozin; Empagliflozin will be taken once daily; Drug: Placebo (matching empagliflozin); Placebo will be taken once daily; Drug: ramipril; Ramipril will be taken once or twice daily
EXPERIMENTAL: Sequence B; Empagliflozin matching placebo followed a wash-out followed by empagliflozin on a background of open label ramipril.	Drug: Empagliflozin; Empagliflozin will be taken once daily; Drug: Placebo (matching empagliflozin); Placebo will be taken once daily; Drug: ramipril; Ramipril will be taken once or twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomerular Filtration Rate (GFR) Under Euglycaemic Conditions After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril.	Glomerular filtration rate (GFR) under euglycaemic conditions after 4 weeks of treatment with either empagliflozin added to ramipril or placebo added to ramipril. The pre-specified statistical analysis was not conducted, because data are too sparse in the subgroup of hyperfilterers.	At week 4 and at week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Filtration Status (Glomerular Filtration Rate (GFR) < 120 mL/Min/1.73m², Yes/no) After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril	Filtration status (Glomerular Filtration Rate (GFR) < 120 mL/min/1.73m²) after 4 weeks of treatment with either empagliflozin added to ramipril or placebo added to ramipril. Filtration status is defined as whether a patient has normal Filtration status (GFR < mL/min/1.73m², "yes") or not (GFR ≥ mL/min/1.73m², "no"). The pre-specified statistical analysis was not conducted, because data are too sparse in the subgroup of hyperfilterers.	At week 4 and at week 12.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Eli Lilly and Company

Publications and helpful links

General Publications

• Lytvyn Y, Kimura K, Peter N, Lai V, Tse J, Cham L, Perkins BA, Soleymanlou N, Cherney DZI. Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition. Circulation. 2022 Aug 9;146(6):450-462. doi: 10.1161/CIRCULATIONAHA.122.059150. Epub 2022 Jul 11.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 10, 2016
• Primary Completion (ACTUAL): December 19, 2017
• Study Completion (ACTUAL): July 2, 2019

Study Registration Dates

• First Submitted: December 15, 2015
• First Submitted That Met QC Criteria: December 15, 2015
• First Posted (ESTIMATE): December 17, 2015

Study Record Updates

• Last Update Posted (ACTUAL): July 24, 2020
• Last Update Submitted That Met QC Criteria: July 23, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Empagliflozin; Ramipril
• Other Study ID Numbers: 1245.100