Renal Effects of Treatment With Empagliflozin Alone or in Combination With Semaglutide in Patients With Type 2 Diabetes and Albuminuria (EmpaSema)

Renal Effects of Treatment With Empagliflozin Alone or in Combination With Semaglutide in Patients With Type 2 Diabetes and Albuminuria - A Double Blinded, Randomised, Placebo Controlled, Parallel, Single Center Study

The objective of this study is to evaluate the effect of treatment with semaglutide 1.34 mg/ml in combination with empagliflozin 25 mg, compared to treatment with empagliflozin 25 mg in combination with placebo on albuminuria in participants with type 2 diabetes and albuminuria.

In a randomised, placebo-controlled, double-blinded, parallel trial we will include 80 patients with type 2 diabetes and albuminuria. Patients will start in a run-in phase of 26 weeks with empagliflozin 25 mg alone. After that, the patients will be randomised 1:1 to an active treatment period with semaglutide of 26 weeks or placebo for 26 weeks.

The primary endpoint is change from randomisation to week 52 in albuminuria, measured in three morning urine samples.

Study Overview

• Status: Unknown
• Conditions: Type 2 Diabetes With Renal Manifestations
• Intervention / Treatment: Drug: Semaglutide, 1.34 mg/mL; Other: Placebo, 1,34 mg/mL; Drug: Empagliflozin 25 MG

Detailed Description

Patients with type 2 diabetes are at high risk of developing diabetic nephropathy. The most promising antidiabetic agents on the market with potential to preserve renal function are endogenous glucagon like peptide (GLP-1) agonists and selective sodium-glucose cotransporter 2 (SGLT2) inhibitors. The LEADER trial demonstrated that treatment with liraglutide (GLP-1 agonist) resulted in 22% lower risk of renal composite outcome. The EMPA-REG trial demonstrated that treatment with empagliflozin (SGLT2 inhibitor) reduced the same renal composite outcome by 39%.

Previous studies have mainly focused on glycaemic parameters when combining a GLP-1 agonist and SGLT2 inhibitor. From a renal perspective, it is of major interest to investigate if a stepwise initiation of semaglutide or placebo added to ongoing empagliflozin therapy would complement or have an additive effect on renal parameters.

In a randomised, placebo-controlled, double-blinded, parallel trial we will include 80 patients with type 2 diabetes and albuminuria. Patients will start in a run-in phase of 26 weeks with empagliflozin 25 mg alone. After that, the patients will be randomised 1:1 to an active treatment period with semaglutide of 26 weeks or placebo for 26 weeks.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Peter Rossing, MD; Phone Number: 30912975; Email: peter.rossing@regionh.dk
• Study Contact Backup: Name: Suvanjaa Sivalingam; Phone Number: 24405599; Email: suvanjaa.sivalingam.02@regionh.dk

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Given written informed consent
2. Male or female patients ≥ 18 years with type 2 diabetes (WHO criteria).
3. UACR > 100 mg/g within a year of informed consent documented in the medical files.
4. eGFR ≥ 30 ml/min/1.73 m2 (estimated by CKD-EPI formula) within 3 months of informed consent documented in the medical files. The eGFR measured at visit 0 has to meet the criteria as well.
5. Fertile female must use chemical, hormonal and mechanical contraceptives, be in menopause (i.e. must not have had regular menstrual bleeding for at least one year), have undergone bilateral oophorectomy or have been surgically sterilized or hysterectomised at least six months prior to screening
6. Treated with maximal tolerated dose of an angiotensin-converting-enzyme inhibitor or an angiotensin II receptor blocker, 4 weeks prior to randomisation. If the participants are not treated with maximal tolerated dosis the investigator will increase the dose 4 weeks prior randomisation if tolerated.
7. Ability to communicate with the investigator and understand informed consent.

Exclusion Criteria:

1. Type 1 diabetes
2. Known or suspected hypersensitivity to trial product(s) or related products
3. Cancer (except basal cell skin cancer or squamous cell skin cancer) or any other clinically significant disorder, except for conditions associated with type 2 diabetes history, which in the investigators opinion could interfere with the results of the trial
4. Cardiac disease defined as: Decompensated heart failure (NYHA class III-IV) and or diagnosis of unstable angina pectoris and/or myocardial infarction within the last 6 months.
5. Previous bowel resection
6. Body mass index < 18.5 kg/m2
7. Females of childbearing potential who are pregnant, breast-feeding, intend to become pregnant or are not using adequate contraceptive methods
8. Known or suspected abuse of alcohol or narcotics.
9. Participant in another intervention study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Semaglutide 1,34 mg/ml; Semaglutide 1,34 mg/ml (solution for subcutaneous injection in pre-filled pen-injector). At randomisation, the participants start with doses of 0.25 mg/week for 4 weeks, then escalate to doses of 0.5 mg/week for 4 weeks, and thereafter escalate to 1.0 mg/week if tolerated until 52 weeks of total treatment.	Drug: Semaglutide, 1.34 mg/mL; After informed consent, subjects will be initiated on open-label empagliflozin 25 mg or maximal tolerated dosis once daily during a run-in period of 26 weeks. Participants will be randomized and up titrated to semaglutide 1.34 mg/ml or matching placebo once weekly during the following 26 weeks in a 1:1 ratio.; Other: Placebo, 1,34 mg/mL; Participants will be randomised to either semaglutide or placebo as an add on treatment after 26 weeks of intervention with empagliflozin 25 mg.; Drug: Empagliflozin 25 MG; After informed consent, subjects will be initiated on open-label empagliflozin 25 mg or maximal tolerated dosis once daily during a run-in period of 26 weeks.
Placebo Comparator: Placebo 1,34 mg/ml; Placebo 1,34 mg/ml (solution for subcutaneous injection in pre-filled pen-injector). At randomisation, the participants start with doses of 0.25 mg/week for 4 weeks, then escalate to doses of 0.5 mg/week for 4 weeks, and thereafter escalate to 1.0 mg/week if tolerated until 52 weeks of total treatment.	Drug: Semaglutide, 1.34 mg/mL; After informed consent, subjects will be initiated on open-label empagliflozin 25 mg or maximal tolerated dosis once daily during a run-in period of 26 weeks. Participants will be randomized and up titrated to semaglutide 1.34 mg/ml or matching placebo once weekly during the following 26 weeks in a 1:1 ratio.; Other: Placebo, 1,34 mg/mL; Participants will be randomised to either semaglutide or placebo as an add on treatment after 26 weeks of intervention with empagliflozin 25 mg.; Drug: Empagliflozin 25 MG; After informed consent, subjects will be initiated on open-label empagliflozin 25 mg or maximal tolerated dosis once daily during a run-in period of 26 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Albuminuria	Change in albuminuria	From randomisation to week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hba1c	Change in Hba1c	From randomisation to week 52
GFR	Change in measured kidney function (GFR)	From randomisation to week 52
24 hour blood pressure	Change in 24 hour blood pressure	From randomisation to week 52
Vasoactive hormones	Change in vasoactive hormones (o Plasma renin concentration, plasma renin activity, angiotensin I, angiotensin II, aldosterone, copeptin)	From randomisation to week 52
Inflammatory and endothelial biomarkers	Change in inflammatory and endothelial biomarkers (Von Willebrand factor, sVCAM-1, sICAM-1, E-selectin, b-leucocytes, s-CRP, IL-6, osteopontin, TNF-α)	From randomisation to week 52

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Novo Nordisk A/S

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2019
• Primary Completion (Anticipated): July 1, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: August 14, 2019
• First Submitted That Met QC Criteria: August 16, 2019
• First Posted (Actual): August 19, 2019

Study Record Updates

• Last Update Posted (Actual): August 19, 2019
• Last Update Submitted That Met QC Criteria: August 16, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Kidney Diseases; Urologic Diseases; Urological Manifestations; Endocrine System Diseases; Diabetes Complications; Urination Disorders; Proteinuria; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Albuminuria; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 2019-003175-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No