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Diabetes and Endocrinology clinical trial

A Phase III, randomised, double blind, placebo-controlled, parallel group, efficacy, safety and tolerability trial of once daily, oral doses Empagliflozin as Adjunctive to insulin over 52 weeks in patients with Type 1 Diabetes Mellitus (EASE-2)

This is a Phase III, randomised, double blind, placebo-controlled, parallel group, efficacy, safety and tolerability trial of once daily, oral doses of Empagliflozin as Adjunctive to insulin therapy over 52 weeks in patients with Type 1 Diabetes Mellitus (known as the EASE-2 study).

The study will be conducted at about 135 study clinics/ hospitals worldwide. About 1440 patients will be screened for suitability and about 720 patients will go on to receive the study medication, with 240 patients assigned to each of the three treatment groups: Empagliflozin 10 mg, Empagliflozin 25 mg and Placebo.

Patients will be required to attend 16 scheduled clinic visits and one telephone visit over approximately 64 weeks. Each visit will take 1-2 hours to complete, depending on what has to be done. Recruitment is competitive. This study is
divided into 5 parts:

i. Screening Period (Visit 1): to determine if the patients are eligible
ii Therapy Optimisation Period (Visits 24T): This period lasts for 6 weeks during which the patient’s current treatment approach will be optimised.
iii. Placebo Run-in Period (Visit 5): in this 2 week period, all patients will take two placebo tablets The tablets will be
taken in addition to insulin.
iv. Randomised Treatment Period (Visits 616):
during this 52 week period, patients will receive study medication, either Empagliflozin or placebo, in addition to their insulin.
v. Follow-Up Period (Visit 17): 3 weeks after the patient has stopped taking the study drug, they will return for a final visit.

Inclusion criteria:
1. Signed and dated written informed consent by the date of Visit 1 in accordance with Good Clinical Practice (GCP)
and local legislation
2. Male or female patient receiving insulin for the treatment of documented diagnosis of T1DM for at least 1 year at the
time of Visit 1
3. Fasting C-peptide
value of < 0.7 ng/mL (0.23 nmol/L) at Visit 2 measured by the central laboratory
4. Use of, and be willing, based on the Investigator’s judgement, to continue throughout the duration of the trial, either:
• MDI of insulin consisting of at least one basal insulin injection and at least three daily bolus injections OR
• CSII of any insulin type, with at least 5 months experience of using CSII prior to Visit 1
For both MDI and CSII, the total daily insulin dose must be ≥ 0.3 U/kg and ≤ 1.5 U/kg at Visit 1
5. HbA1c ≥ 7.5% and ≤ 10.0% at Visit 5 measured by the central laboratory, and provided that the patient’s HbA1c
does not increase by > 0.3% between Visit 1 and Visit 5
6. Based on the Investigator’s judgement patient must have a good understanding of his/her disease and how to
manage it, and be willing and capable of performing the following study assessments (assessed at Visits 1-5
and just before randomisation):
• patient-led management and adjustment of insulin therapy
• reliable approach to insulin dose adjustment for meals, such as carbohydrate counting
• reliable and regular home-based blood glucose monitoring
• recognise the symptoms of DKA, and reliably monitor for ketones
• implementation of an established “sick day” management regimen
7. Age ≥ 18 years at Visit 1
8. Body Mass Index (BMI) of ≥ 18.5 kg/m2 at Visit 1
9. eGFR ≥ 30 mL/min/1.73 m² as calculated by the CKDEPI formula, based on creatinine measured by the central laboratory at Visit 1
10. Women of child-bearing potential* must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Such methods should be used throughout the study and the patient must agree to periodic pregnancy testing during participation in
the trial. A list of contraceptive methods meeting these criteria will be provided in the patient information
*Women of child-bearing potential are defined as follows:
Any female who has experienced menarche and is not post-menopausal (defined as at least 12 months with no
menses without an alternative medical cause) or who is not permanently sterilised (e.g. tubal occlusion, hysterectomy,
bilateral oophorectomy or bilateral salpingectomy)
11. Compliance with trial medication administration must be between 80% and 120% during the openlabel placebo run-in period for calculation of compliance), to be judged before randomisation

Exclusion criteria:
1. History of T2DM, maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis
2. Pancreas, pancreatic islet cells or renal transplant recipient
3. T1DM treatment with any other antihyperglycaemic drug (e.g. metformin, alpha-glucosidase inhibitors, glucagon-like-peptide 1 (GLP-1) analogues, SGLT-2
inhibitors, pramlintide, inhaled insulin, premixed
insulins etc.) except subcutaneous basal and bolus insulin within 3 months prior to Visit 1 or any history of clinically relevant hypersensitivity according to Investigator’s judgement
4. Occurrence of severe hypoglycaemia involving coma and/or seizure that required hospitalisation or hypoglycaemia-related treatment by an emergency physician or paramedic within 3 months prior to Visit 1
5. Occurrence of severe DKA (i.e. a pH of < 7.0 or prolonged Intensive Care Unit [ICU] admission exceeding two days) requiring hospitalisation within 3 months prior to Visit 1
6. Irregular sleep/wake cycle (e.g. patients who habitually sleep during the day and work during the night) based on Investigator’s judgement
7. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or transient ischaemic attack (TIA) within 3 months prior to Visit 1
8. Diagnosis of severe gastroparesis (based on Investigator’s judgement)
9. Diagnosis of brittle diabetes based on Investigator judgement
10. Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal (ULN) at Visit 1 or Visit 5 as measured by the central laboratory
11. Eating disorders such as bulimia or anorexia nervosa
12. Treatment with anti-obesity drugs, weight-loss
surgery or aggressive diet regimen leading to unstable body weight (based on Investigator’s judgement) 3 months prior to Visit 1 and until randomisation
13. Treatment with systemic corticosteroids or planned initiation of such therapy at Visit 1. Inhaled or topical use of corticosteroids (e.g. for asthma/chronic obstructive pulmonary disease) is acceptable
14. Change in dose of thyroid hormones within 6 weeks prior to Visit 1 or planned change or initiation of such a therapy at Visit 1
15. Patient must be willing, based on the Investigator’s judgement, not to take any paracetamol (acetaminophen)
containing drugs throughout the CGM monitoring periods, since this may falsely raise CGM glucose readings
16. Medical history of cancer or treatment for cancer in the last five years prior to Visit 1. Resected basal cell carcinoma considered cured is exempted
17. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia) at Visit 1
18. Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial
19. Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial participation based on Investigator’s judgement
20. Intake of an investigational drug in another trial within 30 days prior to Visit 1
21. Patient not able to understand and comply with study requirements, including the use of an ediary, based on Investigator’s judgement
22. Any other clinical condition that, based on Investigator’s judgement, would jeopardise patient safety during trial participation or would affect the study outcome (e.g. immunocompromised patients who might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections etc.)

Principal Investigator for this trial: Dr Peter Mansell

Research Ethics Committee Reference: 15/EE/0161

Contact us about participating in this study by emailing R& or telephoning 0115 924 9924 Ext. 70076

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