Empagliflozin add-on to Insulin in Type 1 Diabetes Mellitus Over 28 Days

Study Overview
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Brief Summary
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Placebo-controlled, double blind (triple-dummy technique), randomised parallel design comparison of three oral doses (2.5 mg, 10 mg, and 25 mg) of empagliflozin in patients with T1DM as adjunctive therapy to insulin over 28 days. Patients will undergo a 14-day open-label placebo run-in period before randomisation. Background insulin therapy will be kept stable during the first 7 days of the treatment period and will be freely adjusted thereafter.

Official Title
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A 28-day Randomised, Placebo-controlled, Double-blind Parallel Group Phase IIa Trial to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Once Daily Oral Doses of 2.5 mg, 10 mg, and 25 mg Empagliflozin as Adjunctive to Insulin in Patients With Type 1 Diabetes Mellitus (EASE-2)

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Empagliflozin medium placebo
* Drug: Empagliflozin low placebo
* Drug: Empagliflozin low placebo
* Drug: Empagliflozin high placebo
* Drug: Empagliflozin medium
* Drug: Empagliflozin medium placebo
* Drug: Empagliflozin high placebo
* Drug: Empagliflozin high placebo
* Drug: Empagliflozin medium placebo
* Drug: Empagliflozin low placebo
* Drug: Empagliflozin low
* Drug: Empagliflozin high


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed and dated written informed consent Male or female patient receiving insulin for treatment of T1DM for at least 12 months C-peptide < 1.5 ng/mL Age 18 to 65 years HbA1c of 7.5% to 10.5% Multiple daily injections (MDI) of any type of insulin Willing to follow an established and individualized carbohydrate counting method and an insulin administration algorithm Body Mass Index of 18.5 to 35.0 kg/m2 Estimated glomerular filtration rate 60 to 150 mL/min/1.73 m² Able and willing to perform study assessments according to investigator's judgement Compliance with trial drug administration 80% to 120% during run-in period Willing not to take any paracetamol containing drugs during the trial Exclusion criteria: Acute symptomatic urinary tract infection or genital infection, chronic or recurrent cystitis History of type 2 diabetes mellitus, maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis Pancreas, pancreatic islet cells or renal transplant recipient Type 1 diabetes mellitus treatment with any other antihyperglycaemic drug except insulin within last 3 months or history of clinically relevant hypersensitivity Occurrence of hypoglycaemia that required hospitalization or treatment by an emergency physician or paramedic within last 3 months Hypoglycaemia unawareness or frequent episodes of unexplained hypoglycaemia Occurrence of diabetic ketoacidosis that required hospitalization or treatment by an emergency physician or paramedic within last 12 months History of macrovascular disease including cardiovascular, cerebrovascular and peripheral artery disease Autonomic neuropathy with gastroparesis Brittle diabetes Liver disease Treatment with anti-obesity drugs, surgery or aggressive diet regimen leading to unstable body weight Treatment with systemic corticosteroids Change in dose of thyroid hormones within last 6 weeks or planned change or initiation of such a therapy Medical history of cancer or treatment for cancer in the last five years Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells Alcohol or drug abuse that would interfere with trial participation or any ongoing clinical condition that would jeopardize patient's or site personnel's safety or study compliance Intake of an investigational drug in another trial within last 30 days Not able to understand and comply with study requirements Pre-menopausal women who are nursing or pregnant or of child-bearing potential and are not practising an acceptable method of birth control

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin low<br>Empagliflozin low once daily | Drug: Empagliflozin medium placebo<br>* Empagliflozin medium placebo<br>Drug: Empagliflozin high placebo<br>* Empagliflozin high placebo<br>Drug: Empagliflozin low<br>* Empagliflozin low<br>|
| Experimental: Empagliflozin medium<br>Empagliflozin medium once daily | Drug: Empagliflozin low placebo<br>* Empagliflozin low placebo<br>Drug: Empagliflozin high placebo<br>* Empagliflozin high placebo<br>Drug: Empagliflozin medium<br>* Empagliflozin medium<br>|
| Experimental: Empagliflozin high<br>Empagliflozin high once daily | Drug: Empagliflozin medium placebo<br>* Empagliflozin medium placebo<br>Drug: Empagliflozin low placebo<br>* Empagliflozin low placebo<br>Drug: Empagliflozin high<br>* Empagliflozin high<br>|
| Placebo Comparator: Placebo<br>Placebo once daily | Drug: Empagliflozin low placebo<br>* Empagliflozin low placebo<br>Drug: Empagliflozin high placebo<br>* Empagliflozin high placebo<br>Drug: Empagliflozin medium placebo<br>* Empagliflozin medium placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 24 h UGE (g/24 h) After Seven Days of Treatment With Empagliflozin 2.5 mg, 10 mg, or 25 mg, or Placebo | Change of urinary glucose excretion (UGE) (g/24 h) from baseline (refers to the last measurement prior to the first intake of any randomised trial medication) after seven days of treatment with empagliflozin 2.5 mg, 10 mg, or 25 mg, or placebo. The treatment effect was estimated on the basis of the least square mean treatment difference at Day 7 extracted from the primary analysis model. The primary endpoint is exploratory. | baseline (Day -1) and 7 days after first drug administration (Day 7) |