Clinical trial NCT02632747
Conditions: Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2 Obesity
Sponsor: Boehringer Ingelheim
Start date: 2016-05-10; Completion date: 2019-07-02
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
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.

Detailed description:

Arms: arm 1: Empagliflozin followed by a wash-out followed by empagliflozin matching placebo on a background of open label ramipril. arm 2: Empagliflozin matching placebo followed a wash-out followed by empagliflozin on a background of open label ramipril.
Interventions: intervention 1: Empagliflozin intervention 2: Placebo (matching empagliflozin) intervention 3: ramipril
Intervention descriptions: intervention 1: Empagliflozin will be taken once daily intervention 2: Placebo will be taken once daily intervention 3: Ramipril will be taken once or twice daily

Protocol documents:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03608483-05
BI Trial No.:
1245.100
BI Investigational 
Product(s):
Empagliflozin
Title:
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
Brief Title:
Empagliflozin and ACEi– effects on hyperfiltration:  BETWEEN 
Study
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
Fax:  
Principal 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (based on Global Amendment 3)
Version and Date:
Version:  4.0
Date:  03 Jul 2018
Page 1 of 108
Proprietary confidential information.
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
empagliflozin 
Protocol date:
15 Sep 2015
Trial number:
1245.100
Revision date:
03 Jul 2018
Title of trial:
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
Principal Investigator
Phone: 
Fax:
Trial site(s):
Clinical phase:
II
Objective(s):
The main objective of the study is to assess the effect of empagliflozin
versus matching placebo when added to ramipril on reducing glomerular 
hyperfiltration (glomerular filtration rate (GFR) ≥ 135 ml/min/1.73m2) 
under euglycaemic conditions.
Methodology:
Randomised, double blind, double-dummy, placebo controlled, cross-over
exploratory renal mechanistic study with empagliflozin compared to 
placebo added to open label ramipril.  The analysis will be based on 
different GFR sub-groups.  Patients will be classified as a hyperfilterer 
(GFR ≥ 135 mL/min/1.73m2) or normofilterer (GFR <135 mL/min/1.73m2) 
based on their screening GFR.  After patients receive ramipril treatment, 
patients will be categorized as a responder (GFR < 135 mL/min/1.73m2) or 
non-responder (GFR ≥ 135 mL/min/1.73m2).
No. of patients: 
total entered:
Approximately 74 randomised patients
each treatment:
Approximately 37 patients in Sequence A:  period 1 dosing with 25 mg 
empagliflozin added to open-label ramipril*and period 2 dosing with 


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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
empagliflozin 
Protocol date:
15 Sep 2015
Trial number:
1245.100
Revision date:
03 Jul 2018
matching placebo to 25mg empagliflozin added to open-label ramipril*.
Approximately 37 patients in Sequence B:  period 1 dosing with matching 
placebo to 25 mg empagliflozin added to open-label ramipril* and period 
2 dosing with 25 mg empagliflozin added to open label ramipril*.  
Patients will undergo a 4 week wash-out period (empagliflozin or matching
placebo) between period 1 and period 2 dosing while remaining on a 
background of open-label ramipril*.
*Background ramipril treatment:  Patients will be dose escalated to 10 mg 
ramipril or to their maximum tolerated dose.
Diagnosis :
Type 1 diabetes mellitus (T1D), Type 2 diabetes (T2D), or obesity
Main criteria
for inclusion:
Male or female patients at least 18 years of age, diagnosed with T1D, 
T2D or obesity at least 6 months prior to screening, with an HbA1c
between 6.5 to 11%, eGFR ≥60 mL/min/1.73m2 and stable glycaemic 
status.
Test product(s):
empagliflozin
dose:
25 mg, once daily
mode of 
administration:
oral
Comparator products:
Matching placebo to 25 mg empagliflozin
dose:
NA
mode of 
administration:
oral
Background products:
ramipril
dose:
1.25 mg, 5 mg or 10 mg
mode of 
administration:
Oral
Duration of treatment:
Up to 5 week screening period
4 week run-in period:  1 week on 5 mg ramipril followed by 3 weeks on 
10 mg ramipril 
4 week Period 1 dosing
4 week wash-out 
4 week Period 2 dosing
Endpoints
The primary endpoint is GFR under euglycaemic conditions after 4 
weeks of treatment with either empagliflozin added to ramipril or 
placebo added to ramipril.
Secondary endpoint


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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
empagliflozin 
Protocol date:
15 Sep 2015
Trial number:
1245.100
Revision date:
03 Jul 2018
Filtration status (GFR < 120 mL/min/1.73m2; yes/no) after 4 weeks of 
treatment with either empagliflozin added to ramipril or placebo added to 
ramipril
Safety criteria:
Further safety endpoints include:
Incidence of adverse events (AEs)
Changes from baseline in clinical laboratory values
Statistical methods:
Restricted Maximum Likelihood Estimation based Mixed-effects Model 
for Repeated Measures analysis will be used to obtain adjusted means for 
the treatment effects. This model will include treatment and period as 
fixed effects, patient as a random effect and randomisation baseline (visit 
8) as a covariate. Compound symmetry will be used as a covariance 
structure for within-patient variation. The primary analysis will be 
restricted to the subgroup of patients with GFR ≥ 135 mL/min/1.73m2 at 
screening (Visit 4). Other sub-groups will be analysed as secondary 
analyses. Binary endpoints will be analysed using McNemar’s test. 


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FLOW CHART
Trial Period
Screening
Run-in
Period 1 Dosing
Wash 
out
Period 2 Dosing
eEOT
Follow 
up
Visit
1
2
3
4
4a
5
6
7
8
9
10
11
12
13
14
15
16
Study Week
-9
-7
-7
-6
-4
-3
-1
-1
-1
3
4
4
8
11
12
12
Early
13
Study Day 
-63
-49
-43
-42
-28
-21
-7
-2
-1
21
27
28
56
77
83
84
Discn. 
only
91
Preferred time window for visits 
(days)
-18 
to -3
-3
NA
NA
+7
-3
NA
NA
±2
NA
NA
+7
±2
NA
NA
NA
+7
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone Visit
X
X
X
X
Fasting visit
X
X
X
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Physical examination1
X
X
X
X
Vital signs2
X
X
X
X
X
X
X
X
X
Height
X
Weight and waist circumference3
X
X
X
X
X
X
Laboratory tests4
X
X
X
X
X
X
X
X
X
Lipid panel and FPG
X
X
X
X
X
X
Ketone measurement at the site5
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
Biomarker sample collection 
X
X
X
X
Pregnancy test6
X
X
X
X
X
X
X
12 lead-ECG7
X
X
Review in/exclusion criteria20
X
X
X
Diet and exercise counselling8
Continuous
Home monitoring9
Continuous


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Trial Period
Screening
Run-in
Period 1 Dosing
Wash 
out
Period 2 Dosing
eEOT
Follow 
up
Visit
1
2
3
4
4a
5
6
7
8
9
10
11
12
13
14
15
16
Study Week
-9
-7
-7
-6
-4
-3
-1
-1
-1
3
4
4
8
11
12
12
Early
13
Study Day 
-63
-49
-43
-42
-28
-21
-7
-2
-1
21
27
28
56
77
83
84
Discn. 
only
91
Preferred time window for visits 
(days)
-18 
to -3
-3
NA
NA
+7
-3
NA
NA
±2
NA
NA
+7
±2
NA
NA
NA
+7
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone Visit
X
X
X
X
Fasting visit
X
X
X
X
X
X
Modified diet10
X
X
X
X
ABPM11
X
X
X
X
24 hour urine collection12
X
X
X
X
Dispense lithium tablet13
X
X
X
X
Clamped euglycaemia including
assessment of GFR14
X
X
X
X
SNS / arterial stiffness / non-
invasive cardiac output 
monitoring
X
X
X
X
Renal panel15
X
X
X
X
Dispense ramipril16
X
X
X
X
X
Administer IMP(s)17
X
X
X
X
X
X
X
X
X
Randomisation
X
Dispense empagliflozin/
placebo18
X
X
Phone Calls19
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Compliance check
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Trial Period
Screening
Run-in
Period 1 Dosing
Wash 
out
Period 2 Dosing
eEOT
Follow 
up
Visit
1
2
3
4
4a
5
6
7
8
9
10
11
12
13
14
15
16
Study Week
-9
-7
-7
-6
-4
-3
-1
-1
-1
3
4
4
8
11
12
12
Early
13
Study Day 
-63
-49
-43
-42
-28
-21
-7
-2
-1
21
27
28
56
77
83
84
Discn. 
only
91
Preferred time window for visits 
(days)
-18 
to -3
-3
NA
NA
+7
-3
NA
NA
±2
NA
NA
+7
±2
NA
NA
NA
+7
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone Visit
X
X
X
X
Fasting visit
X
X
X
X
X
X
Wash-out of existing RAAS 
therapy21
X
Trial termination
X
1. Screening visit physical examination may be done any time during the screening period prior to the start of ramipril treatment.  
2. At visit 1, BP should be measured in both arms.  If BP differs by more than 10 mmHg, the arm with the higher BP should be 
used for subsequent measurements. For routine clinic visits, systolic and diastolic BP as well as pulse rate should be measured 
3 times after 5 minutes of rest in the supine position.  During renal study visits (visit 4, 8, 11 and 15); BP and pulse will be 
measured 3 times in the supine position (refer to Section 5.2.4). 
3. Weight and waist circumference to be taken in the morning (refer to Section 5.2.5)
4. Routine safety labs include haematology, chemistry and routine urinalysis (A & B) including the local dipstick test for 
leukocyte and/or nitrite. C-peptide, TSH, urine albumin and creatinine will be measured at visit 1 (refer to Table 5.3.3:1).
5. In patients with T1D or patients who are only using insulin for management of diabetes, ketones should be measured at the site 
using the home monitoring device either immediately before or after the collection of laboratory samples.  Ketones can be 
measured in a fasted or non-fasted state.
6. A pregnancy test will be performed in all women of child bearing potential.  More frequent testing can be done if required per 
Investigator judgment.


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7. Additional Electrocardiograms (ECGs) should be performed in cases of cardiac symptoms per Investigator judgment.
8. Patients will be advised to follow a healthy diet and exercise program based on Investigator recommendation during the study;
during the 7 days preceding the start of the renal physiology laboratory assessments patients will be required to follow a 
modified diet (refer to Section 4.2.2.2).  
9. Self-Blood Glucose Monitoring (SBGM) should be performed daily in patients with diabetes.  Measurements should be taken, 
at least before breakfast, lunch, dinner and bedtime in patients with T1D and at least once per day or as directed by the 
investigator, in patients with type 2 diabetes (T2D). Obese patients (without diabetes) are not required to monitor blood sugars 
unless deemed necessary by the investigator. Additional measurements may also be warranted as per the usual care of patients.  
For further details see Section 5.3.2.1.  Ketone measurements should be performed by the patient with T1D daily during the 
screening and treatment periods (excluding run-in and wash-out) and for 5 days after the end of double blind treatment.  In 
case of any symptoms of diabetic ketoacidosis (DKA), more frequent monitoring may be required.  Other conditions may also 
trigger the need for ketone measurement.  Patients with T2D and obesity may measure ketones as per Investigator judgment. 
For further details see Section 5.3.2.2.  Home blood pressure monitoring should be performed daily after starting ramipril.  For 
further details see Section 5.3.2.3.
10. Patient will be instructed to adhere to a sodium enriched (preferably > 140 mmol/day) and moderate-protein (<1.5g/kg/day) 
diet during the 7 days preceding the start of renal assessments during screening, open-label treatment and double-blind 
treatment periods (the diet to continue until the end of renal assessments). Instruction for this diet will be included in the 
patient diary and reinforced by the site via a phone call.  If a patient fails to adhere to the prescribed sodium enriched and 
moderate-protein diet, the Investigator will assess whether the patient is still eligible to start the renal assessments based on the 
patient’s actual diet during the 7 days preceding the renal physiological assessments. In cases of an unsatisfactory diet, patients 
may have to be screen failed based on the Investigator’s judgment. 
11. The ambulatory blood pressure monitor (ABPM) device is initiated on the mornings of the specified visits before study 
medication intake, if applicable. Patient should return to the clinic on the following day to have the device removed after 24 
hours of monitoring has been completed.
12. The 24 hour urine collection should start ideally one day prior to the renal visits (Visits 4, 8, 11 or 15) after the patient has 
been on the modified diet.  Collected urine should be returned to the clinic on the following day.
13. Patients will be required to take a lithium tablet approximately 12 hours prior to Visit 4, 8 11 and 15 for the determination of 
segmental tubular sodium handling.  


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14. Assessments to be performed under euglycaemic conditions (glycaemia maintained between 4-6 mmol/L).  Based on the 
glycaemic status of obese patients, a euglycaemic clamp may not be required based on Investigator judgment.  In the event that 
a patient does not require a euglycaemic clamp, patients will still arrive at the study center in the morning (between 7:45 and 
8:30 am) and will commence the inulin or iohexol and PAH infusion at approximately noon.
Time
Assessments – Inulin Procedure
07:45 – 8:30
Admittance to laboratory and preparation for clamp procedures to maintain 
desired glycaemia (4-6 mmol/l) throughout assessments for that day.  
Investigator to assess if a glycaemic clamp is required for non-diabetic 
patients. 
11:30 – 11:55
Blood and urine samples collected for BHB analysis (to be collected within 30 
min of starting the inulin and PAH infusion).
12:00
Start Inulin and PAH infusion. Study medication(s) to be administered in clinic 
during open label and double blind treatment periods.  Neurohormone levels 
(RAAS mediators, NO), arterial stiffness, NICOM, markers of sympathetic 
nervous system activation (heart rate variability) and other laboratory 
assessments including renal panel samples will be obtained.
13:30-14:00
Continued Inulin and PAH infusion, assessment of MAP and clearance 
measurements (GFR, ERPF, FF, RBF, RVR) each based on the average of 2 
measurements.   
14:00
Continued Inulin and PAH infusion, assessment of MAP and clearance 
measurements (GFR, ERPF, FF, RBF, RVR) each based on the average of 2 
measurements.
Blood and urine samples collected for BHB analysis will be collected 
approximately 2 hours after the administration of study medication.


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Time
Assessments – Iohexol Procedure
07:45 – 8:30
Admittance to laboratory and preparation for clamp procedures to 
maintain desired glycaemia (4-6 mmol/l) throughout assessments for 
that day.  Investigator to assess if a glycaemic clamp is required for non-
diabetic patients.
11:30 – 11:55
Blood and urine samples collected for BHB analysis (to be collected 
within 30 min of starting the ioxhexol bolus).  Iohexol pre-dose sample 
to be collected.
12:00
Administer iohexol bolus infusion. Study medication(s) to be 
administered in clinic during open label and double blind treatment 
periods.  Neurohormone levels (RAAS mediators, NO), arterial stiffness, 
NICOM, markers of sympathetic nervous system activation (heart rate 
variability) and other laboratory assessments including renal panel 
samples will be obtained.
14:00
Assessment of MAP and clearance measurements (GFR, ERPF, FF, 
RBF, RVR) each based on the average of 2 measurements.  Blood 
sample collection for measurement of plasma iohexol, haematocrit and 
pre-dose PAH. Blood and urine samples collected for BHB analysis will 
be collected approximately 2 hours after the administration of study 
medication. Administer bolus of PAH.
14:30
Blood sample collection for measurement of plasma iohexol, 
haematocrit
15:00
Blood sample collection for measurement of plasma iohexol, 
haematocrit
15:30
Blood sample collection for measurement of plasma iohexol, 
haematocrit and PAH


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16:00
Blood sample collection for measurement of plasma iohexol, 
haematocrit and PAH
15. The renal panel (refer to Table 5.3.3:2) and urinalysis C (refer to Table 5.3.3:1) will be performed at visits 4, 8, 11 and 15.  
16. Site staff will dispense ramipril (5 mg) at visit 4a.  Starting at visit 5, patient should be up titrated to 10 mg ramipril.  A lower 
dose of ramipril (e.g. as low as 1.25 mg quaque die (once a day) (q.d.) may be administered based Investigator’s discretion to 
alleviate potential side effects (e.g., hypotension) (refer to Section 4.1.3).
17. Ramipril study medication to be administered in the clinic during visits 4a, 5, 7 and 8 by delegated study staff.  Ramipril and 
empagliflozin/placebo to be administered in the clinic during visits 10, 11, 14 and 15 by delegated study staff.  At visit 12, only 
ramipril will be administered during the clinic visit.
18. At visit 8 and visit 12, site staff will dispense empagliflozin/placebo (but not administer) and instruct patient to start taking the 
empagliflozin/placebo medication starting the following morning (i.e. day 1 or day 57).  
19. Site staff must contact the patient via phone daily for approximately 5 days following the start or dose adjustment of ramipril 
and start or stoppage of empagliflozin/placebo to reinforce compliance (if required), learn of any AEs or determine if the 
patient’s insulin should be titrated.
20. Prior to visit 4a, site staff must review the GFR value obtained from visit 4 and determine if the patient would be eligible to 
enter run-in (visit 4a) in accordance with the recruitment caps outlined in Section 3.3.  
21. If a patient is taking a RAAS inhibitor and may safely discontinue, in the opinion of the investigator, patients may commence a 
wash-out of their prescribed RAAS inhibitor after signing the informed consent form. Refer to Section 6.2.1 for further 
details.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................16
1.
INTRODUCTION...............................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.2
DRUG PROFILE................................................................................................19
1.2.1
Non-clinical assessment of safety.......................................................................20
1.2.2
Clinical pharmacokinetics..................................................................................20
1.2.2.1
Clinical pharmacokinetics – Type 2 diabetes mellitus..........................................20
1.2.2.2
Clinical pharmacokinetics – Type 1 diabetes mellitus..........................................20
1.2.2.3
Clinical pharmacokinetics and pharmacodynamics – comparison in Type 1 vs 
Type 2 diabetes mellitus .......................................................................................20
1.2.3
Clinical efficacy and safety.................................................................................21
1.2.3.1
Clinical efficacy and safety – type 2 diabetes.......................................................21
1.2.3.2
Clinical efficacy and safety – Type 1 diabetes mellitus........................................22
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....24
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................24
2.2
TRIAL OBJECTIVES........................................................................................24
2.3
BENEFIT - RISK ASSESSMENT.....................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................28
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................28
3.1.1
Administrative structure of the trial .................................................................28
3.1.1.1
Clinical Event Committee – severe hypoglycaemia, DKA...................................29
3.1.1.2
Hepatic event adjudication....................................................................................29
3.1.1.3
Clinical Event Committee – cardiovascular events ..............................................30
3.1.1.4
Data monitoring committee ..................................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................31
3.3.1
Main diagnosis for trial entry ............................................................................32
3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Removal of patients from therapy or assessments...........................................35
3.3.4.1
Removal of individual patients .............................................................................35
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................35
4.
TREATMENTS...................................................................................................37


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4.1
TREATMENTS TO BE ADMINISTERED.....................................................37
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........37
4.1.2
Method of assigning patients to treatment groups...........................................38
4.1.3
Selection of doses in the trial..............................................................................38
4.1.4
Drug assignment and administration of doses for each patient......................38
4.1.5
Blinding and procedures for unblinding...........................................................40
4.1.5.1
Blinding.................................................................................................................40
4.1.5.2
Unblinding and breaking the code ........................................................................40
4.1.6
Packaging, labelling, and re-supply...................................................................40
4.1.7
Storage conditions...............................................................................................41
4.1.8
Drug accountability.............................................................................................41
4.1.8.1
Patient treatment compliance................................................................................41
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT.....................................................................................................42
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....42
4.2.2
Restrictions ..........................................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment ......................................................44
4.2.2.2
Restrictions on diet and life style..........................................................................44
5.
VARIABLES AND THEIR ASSESSMENT ....................................................46
5.1
TRIAL ENDPOINTS..........................................................................................46
5.1.1
Primary Endpoint(s)...........................................................................................46
5.1.2
Secondary Endpoint(s) .......................................................................................46
5.2
ASSESSMENT OF EFFICACY........................................................................47
5.2.1
Haemodynamic measurements..........................................................................47
5.2.2
Segmental tubular handling of sodium.............................................................49
5.2.3
Arterial stiffness and sympathetic nervous system (SNS) measurements .....49
5.2.4
Blood pressure (BP) and pulse rate...................................................................49
5.2.4.1
Routine clinic visits...............................................................................................49
5.2.4.2
Renal study visits ..................................................................................................50
5.2.5
Weight and waist circumference .......................................................................50
5.2.6
Ambulatory blood pressure monitoring ...........................................................50
5.2.7
Non-invasive cardiac output monitoring ..........................................................51
5.3
ASSESSMENT OF SAFETY.............................................................................51
5.3.1
Physical examination ..........................................................................................51
5.3.2
Home monitoring ................................................................................................51
5.3.2.1
Self Blood Glucose Monitoring (SBGM).............................................................51
5.3.2.2
Ketone monitoring ................................................................................................52
5.3.2.3
Blood Pressure ......................................................................................................53
5.3.3
Safety laboratory parameters ............................................................................53
5.3.3.1
Follow-up on suspicion for urinary tract infections..............................................56
5.3.4
Electrocardiogram ..............................................................................................57
5.3.5
Other safety parameters.....................................................................................57
5.3.5.1
Assessment of hypoglycaemia rate.......................................................................57


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5.3.5.2
Criteria for hypoglycaemic events........................................................................57
5.3.5.3
Criteria for diabetic ketoacidosis ..........................................................................58
5.3.6
Assessment of Adverse Events ...........................................................................58
5.3.6.1
Definitions of AEs ................................................................................................58
5.3.7
Adverse event collection and reporting.............................................................62
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................63
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................63
5.5.1
Endpoints based on biomarkers ........................................................................64
5.5.2
Methods of sample collection .............................................................................64
5.5.3
Analytical determinations ..................................................................................64
5.5.4
Biobanking...........................................................................................................64
5.6
OTHER ASSESSMENTS...................................................................................64
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................64
6.
INVESTIGATIONAL PLAN.............................................................................65
6.1
VISIT SCHEDULE.............................................................................................65
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................65
6.2.1
Screening and run-in period(s)..........................................................................65
6.2.2
Treatment period(s)............................................................................................67
6.2.2.1
Period 1 dosing......................................................................................................67
6.2.2.2
Wash-out...............................................................................................................67
6.2.2.3
Period 2 dosing......................................................................................................68
6.2.2.4
Unscheduled visits during the treatment period....................................................68
6.2.3
Follow Up Period and Trial Completion...........................................................68
6.2.3.1
Early end of treatment visit (eEOT)......................................................................68
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................70
7.1
STATISTICAL DESIGN – MODEL ................................................................70
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................70
7.3
PLANNED ANALYSES.....................................................................................71
7.3.1
Primary endpoint analyses.................................................................................72
7.3.1.1
Primary Analysis...................................................................................................72
7.3.1.2
Secondary and sensitivity analyses.......................................................................73
7.3.2
Secondary endpoint analyses .............................................................................74
7.3.2.1
Primary Analysis...................................................................................................74
7.3.2.2
Secondary analyses ...............................................................................................74
7.3.4
Safety analyses.....................................................................................................75
7.4
INTERIM ANALYSES ......................................................................................76
7.5
HANDLING OF MISSING DATA ...................................................................76
7.6
RANDOMISATION ...........................................................................................76
7.7
DETERMINATION OF SAMPLE SIZE .........................................................77
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........79


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8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................79
8.2
DATA QUALITY ASSURANCE ......................................................................79
8.3
RECORDS...........................................................................................................79
8.3.1
Source documents ...............................................................................................80
8.3.2
Direct access to source data and documents.....................................................80
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS80
8.4.1
Listedness.............................................................................................................80
8.4.2
Expedited reporting of adverse events..............................................................80
8.5
STATEMENT OF CONFIDENTIALITY........................................................80
8.6 
END OF TRIAL..................................................................................................81
9.
REFERENCES....................................................................................................82
9.1
PUBLISHED REFERENCES............................................................................82
9.2
UNPUBLISHED REFERENCES......................................................................85
10.
APPENDICES.....................................................................................................86
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................87


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ABBREVIATIONS
ABPM
Ambulatory Blood Pressure Monitor
ACEi
Angiotensin Converting Enzyme inhibitor
AE
Adverse Event
AESI
Adverse Events of Special Interest
AIx
Augmentation Index
AP
Alkaline Phosphatase
ARB
Angiotensin II Receptor Blocker
AST
Aspartate Aminotransferase
AUC
Area under the curve
BHB
Beta-hydroxybutyrate
BP
Blood Pressure
cAMP
Cyclic adenosine monophosphate
CEC
Clinical Events Committee
cGMP
Cyclic guanosine monophosphate
CI
Confidence Interval
CKD
Chronic Kidney Disease
Cmax
Maximum concentration
CRA
Clinical Research Associate
CSII
Continuous Sub-Cutaneous Insulin Infusion
DEDP
Drug exposure during pregnancy
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
ERPF
Effective Renal Plasma Flow
ESRD
End Stage Renal Disease
FAS
Full Analysis Set
FPG
Fasting Plasma Glucose
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HbA1c
Glycosylated Haemoglobin
HDL
High Density Lipoprotein
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LDL
Low-Density Lipoprotein
MDI
Multiple Daily Injections
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed-effects Model for Repeated Measures
NICOM
Non-Invasive Cardiac Output Monitoring


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PAH
Paraaminohippurate
PD
Pharmacodynamic
PI
Principal Investigator
PK
Pharmacokinetic
PPS
Per-Protocol Set
q.d.
quaque die (once a day)
RAAS
Renin Angiotensin Aldosterone System
RBF
Renal Blood Flow
REML
Restricted Maximum Likelihood Estimation
REP
Residual Effect Period
RIS
Run-In Set
SAE
Serious Adverse Event
SBGM
Self-Blood Glucose Monitoring
SGLT-2
Sodium dependent Glucose co-Transporter - 2
SNS
Sympathetic Nervous System
SUSAR
Serious Unexpected Suspected Adverse Reaction
T1D
Type 1 Diabetes
TGF
Tubuloglomerular feedback
TS
Treated Set
TSH
Thyroid Stimulating Hormone
UGE
Urinary Glucose Excretion
ULN
Upper Limit of Normal
UTI
Urinary Tract Infection
WBC
White Blood Cell


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Controlling blood glucose in diabetes patients leads to improved patient outcomes [R04-
2186, R12-1489, R04-2173].  Unfortunately despite advances in oral anti-diabetic therapies, 
insulin formulation and delivery and refinement of pharmacokinetic (PK) properties of rapid-
and long-acting insulin analogues, current therapy for patients requiring pharmacotherapy
often does not lead to satisfactory glycaemic control.  In fact, only a minor portion of patients 
achieve normalization of glycosylated haemoglobin (HbA1c) and restoration of euglycaemia.  
Hence with the currently available treatment options, patients with diabetes often fail to 
maintain adequate blood glucose control.  This not only leads to serious acute conditions such 
as severe hypoglycaemia and ketoacidosis but also may lead to debilitating secondary 
complications including heart disease, blindness and kidney failure [R10-6369].  Diabetic 
nephropathy is the most significant cause of renal failure in North America, accounting for 
>40% of cases.  In addition to diabetes, there are other conditions, such as obesity, that 
increases the risk for the development of chronic kidney disease (CKD), including 
progression to end stage renal disease (ESRD) [R18-1327].  The rate of progression from 
CKD to ESRD is also increased in patients with elevated BMI, including those with class II 
obesity and above.  The initial stages of renal disease are characterised by renal 
haemodynamic alterations that result in increased intraglomerular pressure and glomerular 
hyperfiltration.  The pathogenesis of hyperfiltration is complex and involves changes in both 
neurohormonal/vascular factors (the vascular hypothesis) as well as tubuloglomerular 
feedback mechanism (TGF; the tubular hypothesis).  
According to the vascular hypothesis for nephropathy, activation of the neurohormonal 
pathways such as the renin-angiotensin-aldosterone-system (RAAS) promotes renal injury in 
obese patients as well as in patients with diabetes [R10-6368, R96-3187, R18-1328, R18-
1329].  RAAS activation results in persistent vasoconstriction of the efferent arteriole of the 
glomerulus which causes high intraglomerular pressure and renal hyperfiltration (GFR ≥ 135 
ml/min/1.73m2), which is a risk factor for progressive nephropathy and early blood pressure 
(BP) abnormalities [R10-6368, R96-3187].  Current standard therapy against proteinuria and 
early nephropathy therefore includes the blockade of RAAS [R96-3190, R02-0327].  
Unfortunately ACEi and angiotensin II receptor blockers (ARBs) incompletely suppress the 
RAAS.  As a consequence of the incomplete physiological effect on hyperfiltration, RAAS 
inhibitors have failed clinically as a preventative therapy in diabetes as they do not 
completely eliminate renal or cardiovascular complications.  Unfortunately > 25% of T1D 
patients will develop diabetic nephropathy despite RAAS blockade and this risk is increased 
in patients with hyperfiltration [R10-6368, R96-3190]. Similarly in obese patients, long term 
reduction in proteinuria induced by RAAS blockade appears to be exhausted over time, 
particularly in absence of weight loss or if there is further weight gain [R18-1330].
The tubular hypothesis is based on an increase in proximal tubular glucose delivery that is 
due to chronic hyperglycemia in diabetes.  This leads to a maladaptive increase in glucose 
reabsorption along with sodium via the Sodium dependent Glucose co-Transporter - 2
(SGLT-2) in the proximal tubule [P13-16965].  As a result, distal sodium chloride delivery to 
the macula densa is decreased which is sensed as a reduction in effective circulating volume 


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by the juxtaglomerular apparatus causing an afferent renal vasodilatory response.  The 
consequence of this altered TGF results in hyperfiltration and increased intraglomerular 
pressure [R12-5147].  
It was demonstrated nearly four decades ago, that in patients with poorly controlled T1D, the 
maximum tubular reabsorption capacity for glucose was significantly increased, whereas one 
would have suspected that during hyperglycaemia, with increased interstitial and intracellular 
glucose concentrations, the reduced glucose concentration gradient across the basolateral 
membrane of the proximal renal epithelial cell would attenuate glucose efflux [R10-6572].  
This paradoxically increased glucose reabsorption in T1D could be explained by an up-
regulation of glucose transporters, including SGLT-2, which was demonstrated in tubular 
cells cultured from patients with T2D [R10-0703].  The phenomenon of increased glucose 
reabsorption when glucose concentration is elevated could therefore be considered a 
maladapted response to glycosuria in diabetes, since it would rather be desirable for the 
kidney to excrete the filtered glucose load in order to restore normoglycaemia [P11-10364]. 
In the EMPA-REG Outcome Study, inhibition of SGLT2 by empagliflozin, is associated with 
slower progression of kidney disease and lower rates of clinically relevant renal events 
compared with placebo as add-on to standard of care therapy for T2D [P16-06807].
In animals and in humans, inhibition of SGLT-2 reduces renal hyperfiltration by a magnitude 
that is similar to ACEi suggesting a protective decline in intraglomerular pressure [R10-6368, 
P13-16965].  The effect of 8 weeks of treatment with empagliflozin has been studied in 
hyperfiltering patients with T1D [P13-16965]. In this patient population, treatment with 25 
mg empagliflozin reduced renal hyperfiltration by – 33 ml/min/1.73m2 to 139 ± 25 
ml/min/1.73m2 which was statistically significant compared with normofilterer patients.  The 
magnitude of the SGLT-2i effect on hyperfiltration was similar to that achieved with an 
ACEi.  However neither agent alone could abolish renal hyperfiltration [P13-16965]. 
Based on the pathophysiological considerations, use of RAAS inhibition combined with 
SGLT-2i may suppress both the neurohormonal (RAAS) and tubular (SGLT-2) pathways that 
are central to the pathogenesis of early nephropathy.     
1.2
DRUG PROFILE
Empagliflozin is a novel, orally available, potent and selective inhibitor of renal SGLT-2.  
SGLT-2 is a member of a larger group of sodium substrate co-transports, the sodium-glucose 
co-transporter 5 gene family [R05-0939].  Under normoglycemia, glucose is completely 
reabsorbed by SGLTs in the kidney, whereas the re-uptake capacity of the kidney is saturated 
at plasma glucose concentrations higher than approximately 10-11 mmol/L, resulting in 
glycosuria.  This threshold concentration can be decreased by SGLT-2 inhibition
[c01678844-07] with a selectivity approximately 5000-fold over human SGLT-1 (IC50 6278 
nM), responsible for glucose re-absorption in the gut, was calculated for empagliflozin 
[c01678844-07]. Selective inhibition of SGLT-2 reduces renal reabsorption of glucose and 
promotes increased urinary glucose excretion (UGE) resulting in reduction of blood glucose 
levels.
Empagliflozin has been developed for treatment of Type 2 diabetes (T2D) mellitus and has 
received marketing approval in various regions including the European Union, Canada and 
the USA where it is marketed under the brand name Jardiance®.


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1.2.1
Non-clinical assessment of safety
For further information regarding pre-clinical evaluation, please refer to the current version 
of the Investigator’s Brochure (IB) for empagliflozin [c01678844-07].
1.2.2
Clinical pharmacokinetics
1.2.2.1
Clinical pharmacokinetics – Type 2 diabetes mellitus
In healthy volunteers and in patients with T2D, empagliflozin predominantly showed linear 
PK.  Empagliflozin reaches peak levels at approximately 1.5 hours and showed a biphasic 
decline with the terminal elimination half-life of 12.4 hours ranging from 10 to 19 hours.
Empagliflozin exposure increases with renal or hepatic impairment; however, no dose 
adjustment is recommended as the observed changes in exposure were not clinical 
meaningful.  The observations from a Phase I study in patients with renal impairment and 
end-stage renal disease indicate a low efficacy of empagliflozin in patients with severe renal 
impairment and end stage renal disease while efficacy is assumed to be unchanged with 
hepatic impairment. 
No clinically relevant PK interactions were observed with other oral antidiabetic medications, 
warfarin, verapamil, ramipril, simvastatin, digoxin, hydrochlorthiazide, torasemide, 
gemfibrozil, rifampicin, probenecid and oral contraceptives (Microgynon®).  
For further details refer to the current version of the IB for empagliflozin [c01678844-07].
1.2.2.2
Clinical pharmacokinetics – Type 1 diabetes mellitus
To support the development of empagliflozin for the T1D indication, a PK/PD 
(pharmacodynamics) study with a 4 week treatment duration has been completed (Trial 
1245.78 – EASE-1), [c02435449-01].  Empagliflozin daily doses of 2.5 mg, 10 mg and 25 
mg were evaluated in this trial.  
Empagliflozin was rapidly absorbed after oral dosing with median tmax around 1.5 hours for 
all empagliflozin dose groups.  Dose-normalised AUC (area-under-the-curve) and Cmax were
similar for all doses after a single dose and at steady-state, demonstrating a dose-proportional 
increase in empagliflozin plasma exposure.  The accumulation ratio (AUC) ranged from 1.04 
to 1.2, indicating limited accumulation of empagliflozin in plasma at steady-state.  Terminal 
half-life was 12 to 16 hours after multiple doses.  The inter-subject variability was low for but 
AUC and Cmax, with a gCV% between 21.8% and 31.3%.  The cumulative amount of 
empagliflozin excreted in urine was comparable on both Days 1 and 28 of treatment, with 
15% to 20% of the dose excreted in urine across the 2.5 mg to 25 mg dose range.
1.2.2.3
Clinical pharmacokinetics and pharmacodynamics – comparison in Type 1 vs 
Type 2 diabetes mellitus
Empagliflozin PK/PD has been compared in patients with T1D versus T2D.  Two 4 weeks 
trials were used: trial 1245.78 (EASE-1) in patients with T1D using empagliflozin daily 
doses of 2.5 mg, 10 mg and 25 mg, and trial 1245.4 in patients with T2D evaluating 
empagliflozin 10 mg, 25 mg and 100 mg. 


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In both patient populations, empagliflozin was rapidly absorbed reaching peak levels in 
approximately 1.5 hours post-dose.  Thereafter, plasma levels declined in a biphasic fashion.  
There were no clinically relevant differences in empagliflozin exposure (AUC and Cmax) 
between the two populations and the terminal elimination half-life appeared to be similar.  
Renal clearance and fraction of empagliflozin excreted in urine were also similar.  
Empagliflozin exposure increased in a dose proportional manner over the dose range tested in 
both studies.  
In both patient populations, oral administration of empagliflozin results in increased UGE at 
all dose levels.  Following a 4 week treatment, increases in UGE from baseline were 
approximately 78 g, 103.1 g and 101.5 g with 2.5 mg, 10 mg and 25 mg empagliflozin once 
daily, respectively, in patients in T1D and 64.4 g, 78.4 g and 72.6 g with 10 mg, 25 mg, and 
100 mg empagliflozin once daily, respectively in patients with T2D.  Results indicate that 
increases in UGE reached a plateau with empagliflozin 10 mg once daily in both populations.  
In addition, preliminary exposure – response analysis showed that approximately 56%, 77%, 
87% and 95% of maximal effect on UGE was achieved with 2.5 mg, 5 mg, 10 mg and 25 mg 
empagliflozin once daily, respectively, indicating that near maximal effects on UGE in 
patients with T1D were observed with empagliflozin 10 mg and 25 mg once daily.  
Overall, there were no clinically relevant differences in PK/PD of empagliflozin in patients 
with T1D compared with T2D.  Empagliflozin PK was similar between the two populations 
and drug exposure increased in a dose proportional manner over the dose range evaluated.  
Increased UGE was observed following oral administration of empagliflozin at all dose levels 
and appeared to reach a plateau at empagliflozin 10 mg once daily in both populations 
[c02435449-01].
1.2.3
Clinical efficacy and safety
1.2.3.1
Clinical efficacy and safety – type 2 diabetes
Approximately 550 healthy volunteers were exposed to empagliflozin (up to 800 mg single 
dose and up to 50 mg qd). In addition, approximately 250 patients with T2D included in 
phase I trials received multiple dosing with empagliflozin up to 100 mg. Overall 
approximately 6900 patients with T2D have been treated with empagliflozin for at least 24 
weeks. Of those patients, approximately 4900 patients have been treated for 52 weeks and 
approximately 2800 patients have been treated for at least 76 weeks.    
The phase III studies have shown that treatment of empagliflozin 10 mg or 25 mg once daily 
for up to 24 weeks results in a reduction of HbA1c up to 0.85%, body weight up to 2.2 kg and 
SBP up to 4.8 mmHg compared to placebo. This was consistently observed with
empagliflozin as monotherapy, add on to metformin, to metformin + sulphonylurea, to
pioglitazone with or without metformin, and to basal insulin with metformin and/or
sulphonylurea. Phase III studies up to 104 weeks in T2D support the sustained effect of 
empagliflozin.
In clinical studies, empagliflozin was well tolerated in both normal healthy volunteers and
patients with T2D up to maximal treatment duration of 104 weeks in completed studies. The 
frequency of overall adverse events (AEs), AEs leading to discontinuation and Serious 
Adverse Events (SAEs) were comparable to placebo. There was no significant increase in 


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frequency of hypoglycaemia with empagliflozin compared to placebo except when used in 
combination with a sulphonylurea or basal insulin. In general, there was a small increase in 
frequency of urinary tract infection (UTI) compared to placebo.  There was an increase in 
frequency of genital infections with the use of empagliflozin.  There was a small increase in 
total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein 
(HDL) cholesterol and no significant changes in triglycerides.  No changes in electrolytes 
were observed with empagliflozin. There was a reduction in estimated Glomerular Filtration 
Rate (eGFR) which gradually returned toward baseline values over the treatment period in 
the trials. Furthermore, eGFR returned to baseline when empagliflozin was discontinued.  In 
a dedicated study in patients with moderate renal impairment (eGFR between 30-60 
ml/min/1.73 m2) treatment with empagliflozin was well tolerated and lead to statistically 
significant reduction of HbA1c and clinically meaningful improvements in fasting Plasma 
Glucose (FPG), body weight and BP compared to placebo at week 24.  Similar results were 
sustained for up to 52 weeks [c01678844-07].
1.2.3.2
Clinical efficacy and safety – Type 1 diabetes mellitus
Two trials have been completed in patients with T1D. The first completed trial was Trial 
1245.46 (ATRIMA), which assessed the impact of 8 weeks of treatment with once daily 
empagliflozin 25 mg on renal hyperfiltration [c01802271-02].  The second completed trial 
was Trial 1245.78 (EASE-1), a 4 week PK and PD trial, which assessed 3 doses of 
empagliflozin (2.5 mg, 10 mg and 25 mg) compared with placebo on 24-hour UGE and other 
glycaemic parameters after 7 days and 28 days [c02435449-01].
In 1245.46, which was an uncontrolled open-label pilot trial, empagliflozin taken for 8 weeks 
as adjunctive to insulin therapy was generally well-tolerated; 42 patients took empagliflozin 
and 40 successfully completed the study.  Two patients prematurely discontinued from the 
trial due to DKA; one case occurred concurrently with gastroenteritis, and the other case 
followed insulin pump malfunction; both patients recovered from DKA.  After 8 weeks of 
treatment in this trial, the mean change (SE) in GFR with empagliflozin 25 mg once daily in 
the hyperfilterer group was -33.4 (6.2) mL/min/1.73 m2 from a baseline of 172.2 
mL/min/1.73 m2 under euglycaemia (p<0.0001) and -44.5 (7.1) mL/min/1.73 m2 from a 
baseline of 186.4 mL/min/1.73 m2 under hyperglycaemia (p<0.0001).  In contrast, the mean 
GFR did not change significantly in non-hyperfilterer patients at the end of treatment.  It was 
therefore concluded that short-term treatment with empagliflozin attenuated renal 
hyperfiltration in patients with T1D, possibly by affecting tubular-glomerular feedback 
mechanism.   
Empagliflozin was also evaluated in this trial for its potential efficacy on glycaemia and rates 
of hypoglycaemia in patients with T1D as an adjunctive to insulin therapy.  After 8 weeks of 
treatment with empagliflozin, a clinically significant mean (SE) increase in UGE of 114.6 
(9.2) g/day was observed from a baseline value of 18.9 g/day.  Based on the 40 patients who 
completed 8 weeks of empagliflozin treatment, the mean change (SE) in HbA1c from baseline 
to end of treatment was -0.40 (0.08)% from a mean baseline HbA1c (SD) of 8.03 (0.91)%.  
The mean change (SE) in FPG from a baseline mean (SD) of 10.01 (4.87) mmol/L was -1.39 
(0.73) mmol/L.  Symptomatic hypoglycaemia (defined by a blood glucose value of < 3.0 
mmol/L based on Home Blood Glucose Monitoring) declined from a mean of 0.12 events per 
day in the 2 week placebo run-in period to 0.04 events per day in the last 2 weeks of the 


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treatment period.  The mean change (SE) in total daily insulin dose at the end of treatment 
was approximately -8.9 (1.7) units/day from a baseline mean (SD) of approximately 54.7 
(20.4) units/day primarily driven by a reduction in basal insulin.  Decreased total insulin 
requirements were observed, despite patient-reported increased carbohydrate intake during 
the same periods; mean change (SE) of 53.78 (14.56) grams per day from a mean (SD) 
baseline value of 176.82 (121.09) grams/day.
These exploratory glycaemic results showed that the addition of empagliflozin 25 mg once 
daily to insulin in the treatment of T1D resulted in an HbA1c reduction after 8 weeks, 
accompanied by a reduction in hypoglycaemic events, reduce insulin requirements and 
reduced glucose variability.  The safety profile did not show any unexpected AE trends in the 
small population studied in this uncontrolled pilot trial [c01802271-02].  
In trial 1245.78, a randomised, double-blind, placebo-controlled, parallel group trial, UGE 
increased from baseline to day 7 for all empagliflozin doses compared with placebo with a 
maximum UGE increase of around 100 g/24 hour in the empagliflozin 10 mg and 25 md dose 
groups.  UGE values continued to increase until the end of the treatment period.  In this 
study, 75 patients took empagliflozin or placebo and all of them successfully completed.  
Other relevant conclusions drawn from the study were as follows [c02435449-01]:

An overall improvement was seen in glycaemic control with empagliflozin treatment 
compared with placebo.  This was reflected by: (i) a reduction in HbA1c compared with 
placebo for all 3 doses of empagliflozin from baseline to Day 28, with the greatest 
reduction (0.49%) observed in the empagliflozin 25 mg group; (ii) a reduction in the 
recorded total daily insulin dose of > 10% at week 4 with empagliflozin treatment 
compared with placebo.

Treatment with empagliflozin over 28 days as adjunctive therapy to multiple daily 
injections (MDI) of insulin was well tolerated. More than 90% of patients were reported 
with hypoglycaemic events, of either mild or moderate intensity.  No cases of DKA were 
reported; numerical increases in beta-hydroxybutyrate (BHB) values from baseline to last 
value on treatment were seen in all empagliflozin dose groups.  After 4 weeks, following 
an insulin-adjustment period (day 8 to day 28), treatment with empagliflozin in patients 
with T1D resulted in a numerically lower frequency of patients symptomatic 
hypoglycaemia with plasma glucose < 54 mg/dL (< 3.0 mmol/L) compared with placebo 
without any hypoglycaemic episodes requiring assistance reported for empagliflozin.
In summary given the safety profile in the pre-clinical studies of empagliflozin, and the 
safety, tolerability and efficacy seen in the clinical study programs to date, the available 
clinical and non-clinical data support safe and efficacious use in humans and further 
development of empagliflozin in T1D and T2D patients.  
For further details please see the current version of the empagliflozin IB [c01678844-07]
which is included in the Investigator Site File (ISF). 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Patients with diabetes or obesity are at greater risk of developing nephropathy, potentially 
leading to end stage renal disease.  The pathophysiology of these complications may be 
partially mediated by activation of the RAAS leading to renal haemodynamic abnormalities 
including efferent arteriolar vasoconstriction, an event which is postulated to result in renal 
hyperfiltration ultimately culminating in organ injury.  Inhibition of the RAAS with an ACEi 
will reduce GFR in patients with diabetes and renal hyperfiltration  and in non-diabetic obese 
patients but does not completely normalize the GFR under euglycemic conditions in all 
patients.  Although patients with hyperfiltration may have an upregulated RAAS, other 
physiological factors are influencing the intraglomerular pressure and filtration rate.  
During chronic hyperglycaemia, there is increased glucose and sodium re-absorption via 
SGLT-2 which results in decreased sodium delivery to the macula densa.  This results in 
increased afferent renal vasodilation, increased intraglomerular pressure and renal 
hyperfiltration.  Blockade of sodium reabsorption at the proximal tubule of the nephron via 
SGLT-2i reverses this effect and has been shown to reduce renal hyperfiltration [c01802271-
02, P13-16965].  The magnitude of this effect, however, is similar to that of ACEi (i.e. 
around 33 ml/min/m2) and does not completely normalize filtration rate.
This study is designed to determine if therapy with SGLT-2i (empagliflozin) added to
ramipril (ramipril) will result in normalization of filtration rate.  Since eGFR measurements 
are unreliable in providing accurate estimates of actual GFR, actual GFR will be measured 
using direct, measured clearance techniques under conditions of euglycaemia.
2.2
TRIAL OBJECTIVES
The main objective of the study is to assess the effect of empagliflozin versus matching 
placebo when added to ramipril on reducing glomerular hyperfiltration GFR ≥135 
ml/min/1.73m2) under euglycaemic conditions.
Other exploratory objectives of the study will investigate the effect of adding empagliflozin 
versus matching placebo when added to ramipril on:

segmental tubular sodium (Na+) handling

distal Na+ delivery and impact on afferent vasoconstrictors such as adenosine

diurnal and nocturnal BP lowering based on ambulatory BP monitoring (ABPM) and,

non-invasive determinants of cardiac output (see to Section 5.2.7), systemic vascular 
resistance and arterial stiffness.
2.3
BENEFIT - RISK ASSESSMENT
The overall safety and tolerability profile of empagliflozin is outlined in Section 1.2.3.  
Ramipril is approved for use in Canada and ACEi, including ramipril, are often used as first 


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line therapy to prevent the onset and progression of nephropathy in patients with diabetes.  
The current IB for empagliflozin supports chronic administration to patients with diabetes.  
Inclusion of patients who do not have diabetes is also allowed in this trial. It has been shown 
that in healthy volunteers dosing with empagliflozin results in glycosuria summing up to 
about 2/3 the average glucosuria in patients with T2DM.  This is similar to the amount of 
glucose lost in T2DM subjects with moderate renal impairment. 
There are no long-term safety data for empagliflozin in patients without diabetes.  Data in 
non-diabetic subjects is limited to healthy volunteers, without significant co-morbidities or 
concomitant medications.  Exposure in healthy volunteers is from single dose and multiple 
dose studies with exposure up to 28 days.  However, while limited, such data does include 
over 500 healthy volunteers exposed to empagliflozin during the clinical development for 
treatment of T2DM. No specific safety concern was identified and no occurrences of 
symptomatic hypoglycemia were detected [U12-2707-01]. It is noted that in patients with 
T2DM the risk of hypoglycemia was only increased with empagliflozin compared to the 
placebo group in patients who were concomitantly treated with insulin or a sulfonylurea.  
Further, in a mechanistic study [c11963611-01], subjects without DM were shown to increase 
endogenous glucose production in response to glucosuria after administration of 
empagliflozin.  As a result, blood glucose levels remained in the normal range for these 
individuals [P16-01830]. Therefore, it is scientifically reasonable to hypothesize that in non-
diabetic patients, with no medical indication for insulin or sulfonylurea treatment that the risk 
of hypoglycemia associated with empagliflozin treatment would be lower than in patients 
with T2DM.  
Because the mode of action, blockade of the SGLT2 with consequent glucosuria, and 
natriuresis, is the same in patients with and without diabetes, although to different degrees, it 
is considered likely that the tolerability of empagliflozin is likely similar in patients without 
DM compared to patients with T2DM.
The Principal Investigator (PI) and 
 team have extensive experience with the techniques 
required to conduct this study.  The PI has conducted previous studies in patients with 
diabetes with ACEi as well as recently completed an 8 week proof-of-concept study that 
demonstrated that treatment with empagliflozin reduces renal hyperfiltration [c01802271-02].  
In this trial, all patients will receive ramipril.  Ramipril is generally well tolerated and has a 
well-defined safety profile. The initial starting dose will be 5 mg and patients will be up 
titrated to 10 mg after one week of treatment.  All patients must meet the BP eligibility 
criteria at the start of the trial.  During the course of the study, patients will receive a home 
BP monitor so that they can check their BP daily.  In addition, patients will have their BP, 
renal function and electrolytes checked prior to initiating treatment and during treatment with 
ramipril.  To mitigate the potential risk of hypotension, patients who are unable to tolerate the 
10 mg q.d. may be dose reduced to a lower dose, with the lowest possible dose being 1.25 mg 
q.d. based on Investigator judgment. It is expected that some patients with hyperfiltration at 
screening may benefit from the ramipril treatment and their GFR may be reduced to < 135 
mL/min/1.73m2 whereas some patients may not respond to ramipril and their GFR will be ≥
135 mL/min/1.73m2 (hyperfilterer) after treatment with ramipril [R10-6368].  
During the course of the study, all patients will receive empagliflozin during one of the two 
treatment periods.  Although the treatment period is short, patients may receive short-term 


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benefit from the positive glycaemic and weight reduction effects of empagliflozin.  In the 
1245.78 trial (EASE-1), it was demonstrated that patients treated with empagliflozin had a 
0.49% placebo-corrected decrease in HbA1c compared to those patients on placebo after only 
4 weeks of treatment (p < 0.05).  In addition patients treated with empagliflozin had a > 10% 
reduction of the total daily insulin dose as well as weight loss after 4 weeks of treatment with 
empagliflozin treatment compared with placebo.  
The rate of hypoglycaemia induced by insulin may not be aggravated by empagliflozin since 
glomerular filtration is physiologically decreased during episodes of severe hypoglycaemia 
(due to reduced renal blood flow hence leading to lowering of urine glucose excretion and 
therefore efficacy of empagliflozin).  Nonetheless, during the treatment periods, patients will 
be closely monitored for hypoglycaemic episodes through self-glucose monitoring (including 
overnight glucose monitoring) and through contact with the study staff, who will call the 
patients daily for approximately 5 days after the start or stoppage of blinded empagliflozin / 
placebo treatment or after ramipril dose adjustment.  Patients will be educated on the signs 
and symptoms of hypoglycaemia as well as trained on the proper use of the self-glucose 
monitoring devices that will be provided through the trial.
This is a placebo-controlled trial and due to the cross over design, all patients will receive the 
empagliflozin matching placebo.  During treatment with placebo, patients will not receive 
additional benefit, however the impact on their glycaemic control is considered to be minimal 
as all patients will continue to follow an appropriate Investigator-recommended diabetes 
treatment algorithm in order to achieve optimal and individualised glycaemic goals.  
The combined effect of the ACEi and SGLT-2i is expected to reduce or potentially normalize 
hyperfiltration in patients with  renal hyperfiltration.  Although long term or sustained benefit 
from short term treatment is unlikely, the information gathered in this study would be proof-
of-concept to further evaluate the potential renal benefits of empagliflozin in patients with 
diabetes in longer term studies and in larger patient populations.  
Normofiltering patients (GFR = 90-134 ml/min/1.73m2) will also be included in this trial.   It 
is expected that renal haemodynamic function (and sodium handling) with ramipril versus 
empagliflozin added to a background of ramipril will remain largely unchanged in this group 
based on results from the ATIRMA trial (1245.46) [c01802271-02] and a study with RAAS 
inhibition with enalapril [R10-6368].  Inclusion of these patients will allow for direct 
comparisons between patients with renal normofiltration versus patients with renal 
hyperfiltration rather than referencing “historical” controls. Given that the potential risk to 
renal haemodynamic function and sodium handling is low and that patients with 
normofiltration will be carefully monitored throughout the study, some patients with 
normofiltration will be included in this trial.
In patients with diabetes, special attention will be paid to prevent DKA as outlined below.  
Due to its mechanism of action, empagliflozin may potentially modify the clinical 
presentation of DKA.  Diabetic patients who are treated with insulin and receiving 
empagliflozin are at risk to underestimate their need for insulin if blood sugar levels are 
within individual target ranges or only slightly elevated.  Insulin deficiency might lead to 
ketoacidosis which could be life-threatening if not recognised and appropriately treated.  All 
diabetic patients will be made aware of this risk and those diabetic patients utilizing insulin to 
manage their diabetes will be instructed not to reduce their insulin dose below Investigator 


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recommendations.  In addition to frequent blood glucose monitoring, patients will measure 
ketones at least daily when treated with empagliflozin, including for 5 days after stopping the 
empagliflozin / placebo treatment.  More frequent ketone monitoring will be performed in 
case of any symptoms of DKA, i.e. nausea, vomiting and abdominal pain.  Patients will be 
instructed to do this irrespective of the glucose value in the event of DKA symptoms 
occurring.  A ketone meter will be provided to the patient for this purpose.  Patients will be 
taught how to interpret ketone values measured by the meter, and on appropriate action to be 
taken in the event of increased ketone levels (see Section 5.3.2.2).  In addition, patients will 
be reminded about insulin adjustment during “sick days” and about the importance of 
keeping themselves hydrated.
Investigators should also differentiate deteriorating ketosis/DKA from any mild to moderate 
increase of ketones which may be seen due to the mechanism of action of empagliflozin, 
especially in the fasted state (e.g. in the morning).  See also Section 1.2.3.2.
As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration when ramipril or empagliflozin are administered.  Angioedema has been 
reported in 0.1% of patients taking ramipril in clinical studies.  Patients who have a history of 
angioedema would be excluded from participating in the study and any patient who 
experiences angioedema while on treatment should immediately stop taking ramipril.
Women who are of child-bearing potential will only be included in this study provided if they 
are using highly effective methods of contraception (c.f. Section 3.3.3).  In the embryo-fetal 
and fertility studies in rats and rabbits, empagliflozin had no effects on early embryonic 
development, mating, male and female fertility, and only a moderate reversible effect on 
body weight of bearing live young were observed up to a dose of 300 mg/kg.  However, use 
of ramipril during pregnancy and breastfeeding is contraindicated because ramipril can cause 
fetal and neonatal morbidity and mortality.  These risks will be mitigated through ensuring 
that patients understand the requirement and will use highly effective methods of 
contraception throughout the conduct of the study.   Pregnancy testing will be conducted on 
all women of child bearing potential during the study.
All patients may derive general medical benefit from the careful and close monitoring by 
medical personnel during the study.  Safety will be carefully assessed by monitoring the 
patients for AEs clinically, by laboratory testing and by blood glucose and ketone monitoring. 
The Investigator will have the discretion to remove patients from the study should there be 
any safety concerns or if the patient’s wellbeing is in jeopardy.  
Other risks to the patients are the risks inherent to any clinical trial such as unexpected 
adverse clinical event.  
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.3.6.1.
Given the favourable safety and tolerability profiles of both ramipril and empagliflozin, the 
careful monitoring of patients during the study and the ability to adjust the insulin 
requirements based on need, the sponsor considers the benefit-risk assessment of this trial to 
be favourable. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This double-blind, placebo-controlled, cross-over design exploratory study aims to evaluate 
the impact of adding empagliflozin or placebo to open label ramipril on GFR under 
euglycaemic conditions in patients with or without renal hyperfiltration. Randomisation to 
blinded treatment will not be stratified according to baseline GFR.
On specified study days, patients will be admitted to the renal physiology lab where their 
renal and systemic vascular functions will be assessed under controlled conditions of 
euglycaemia.  Assessments will be conducted at screening (day -42), run-in (day -1) and 
study days 28 (period one dosing) and 84 (period two dosing).  Patient participation is 
concluded when a patient has completed the last planned study visit.  The end of the trial is 
defined as the “last patient out” (i.e. the last Visit 16 completed by the last patient in the 
trial). For a graphical representation of the trial, see Figure 3.1:1 below.
Figure 3.1:1
Trial Design
Please refer to Section 5.3.6 for assessment of AEs and Section 5.3.7 for AE collection and 
reporting.
3.1.1
Administrative structure of the trial
This trial is sponsored by Boehringer Ingelheim Canada Ltd.
Boehringer Ingelheim will appoint a Trial Clinical Monitor, responsible for coordinating the 
activities required in order to manage the trial in accordance with applicable regulations and 
internal Standard Operating Procedures (SOPs), directing the clinical trial team in the 
preparation, conduct, and reporting of the trial, order the materials as needed for the trial, 


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ensures appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and investigators of participating countries.
Data Management and Statistical evaluation will be done by BI according to BI SOPs. For 
these activities, a Trial Data Manager and a Trial Statistician will be appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons will be given in the Trial Master 
File (TMF) document.
The organisation of the trial in Canada will be done by the local BI-organisation. A CML will 
be appointed responsible for coordinating the activities required in order to manage the trial 
in accordance with applicable regulations and internal SOPs.
Documents on PI and other important participants, especially their curricula vitae, will be 
filed in the TMF document. 
Details on handling of the trial supplies including responsible institutions are given in Section
4 of this protocol.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in IRT Manual and Central Laboratory Manual, available in ISF.
The ISF document will be kept in print-out version at the site as far as required by local 
regulation and BI SOPs. A copy of the ISF documents will be kept as an electronic TMF 
document according to BI SOPs.
3.1.1.1
Clinical Event Committee – severe hypoglycaemia, DKA
An independent external committee (Clinical Event Committee or CEC) will be established 
to adjudicate centrally and in a blinded fashion events suspect of severe hypoglycaemia (for 
further details see Section 5.3.5.2) and DKA (for further details see Section 5.3.5.3).  The 
CEC will evaluate whether pre-specified criteria for adjudication endpoints are met.  
For any events that qualify for adjudication, the study site will be asked to provide clinical 
documentation such as laboratory values, discharge summaries etc. to support the external 
event adjudication. 
The tasks and responsibilities of the CEC will be specified in a charter.  The CEC will 
maintain the adjudication results in writing.  
3.1.1.2
Hepatic event adjudication 
Certain hepatic events will be adjudicated/assessed by external independent experts for 
severity and causal relationship with the trial medication; in a blinded fashion.  The events 
which will be reviewed will be defined in a charter. Events may be defined by abnormal 
laboratory values and/or relevant AEs or both.  For qualifying events, relevant source 
documents generated from any medical evaluations of these events will be requested 
including laboratory values, hospital discharge letters, and medical reports from other 
physicians, if applicable.  All evaluations will be performed in a blinded fashion. The 
assessments will be analysed based on empagliflozin data combined from multiple trials (i.e., 
on a project level).


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3.1.1.3
Clinical Event Committee – cardiovascular events
An independent external committee (Clinical Events Committee, CEC) will be established to 
adjudicate centrally and in a blinded fashion events suspect of stroke, myocardial ischaemia 
(including myocardial infarction), cardiovascular death and other relevant events (e.g., 
hospitalisation for unstable angina, hospitalization for heart failure) based on the FDA 
guideline [R09-2151].  The CEC will evaluate whether pre-specified criteria for adjudication 
endpoints are met.  
For any events that qualify for adjudication, the study site will be asked to provide clinical 
documentation such as ECGs, laboratory values, angiography, echocardiography reports, CT 
and/or MRI scans, discharge summaries, and autopsy reports to support the external event 
adjudication. 
The tasks and responsibilities of the CEC will be specified in a charter.  The CEC will 
maintain the adjudication results in writing.  
3.1.1.4
Data monitoring committee
A data-monitoring committee (DMC), independent of the Sponsor, will be established to 
assess the progress of the clinical trial, including an unblinded safety assessment at specified 
intervals, and to recommend to the Sponsor whether to continue, modify, or stop the trial. 
Measures are in place to ensure blinding of the Sponsor and all other trial participants. The 
tasks and responsibilities of the DMC will be specified in a charter. The DMC will maintain 
written records of all its meetings.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is a mechanistic study where patients will receive open-label ramipril and then are 
randomised to either Sequence A (period 1 dosing with 25 mg empagliflozin and period 2 
dosing with matching placebo to 25 mg empagliflozin) or Sequence B (period 1 dosing with 
matching placebo to 25 mg empagliflozin and period 2 dosing with 25 mg empagliflozin).  
Patients will undergo a 4 week wash-out period between period 1 and period 2 dosing.  The 
trial is designed to assess the additive effect of empagliflozin added to RAAS inhibition on
renal function under conditions of euglycaemia. 
The cross-over design was selected since each patient will act as their own control and will 
therefore reduce the variability in the data.  It is not expected that there will be significant 
sequence effect since, based on previous research, it is expected that the hemodynamic 
changes resulting from the treatments will occur rapidly and the 4 week wash-out period is 
long enough to ensure that any effects from the previous treatment sequence have diminished 
to baseline.  
All eligible patients will be started on ramipril during a 4 week open-label run-in period.  
RAAS inhibition, including ACEi therapy, is the current standard of care to slow down the 
progression of diabetic kidney disease.  Therefore ramipril therapy was selected as the 
background treatment in this study.  Recommended starting dose is 5 mg q.d. ramipril with 


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titration up to 10 mg dose of ramipril after 1 week of treatment and will remain preferably on 
10 mg ramipril for the remainder of the study.   
Patients who are eligible to be randomised will be randomly assigned to either Sequence A or 
Sequence B in a blinded manner.  It is expected that patients will continue to take 10 mg 
ramipril during both period 1 and period 2 dosing and throughout the 4 week wash-out that 
will separate each dosing period.  It is expected that any changes to renal function would be 
seen after 4 weeks of randomised treatment.
Although all patients will be randomised to one of two treatment sequences, patients will be 
defined as either a hyperfilterer (GFR is ≥ 135 mL/min/1.73 m2) or normofilterer (GFR is < 
135 mL/min/1.73 m2) based on their GFR during the screening period (visit 4).  Additionally, 
patients will be categorised as either a responder to ramipril treatment (i.e., GFR is < 135 
mL/min/1.73 m2) or a non-responder to ramipril treatment (i.e., GFR is ≥135 mL/min/1.73 
m2) based on their GFR at the end of run-in (visit 8).  The planned efficacy analysis will be 
conducted based on these sub-groups as it has been found in a previous study that the 
response to empagliflozin is strongly correlated with the baseline GFR measurement
[c01802271-02].  Randomisation will not be stratified based on these sub-groups due to 
several reasons.  Each randomized patient will receive empagliflozin treatment as well as the 
matching placebo and the order in which these treatments are administered is not expected to 
influence the GFR results due to the lengthy wash-out period.  Given that a cross over design 
is employed and each patient will act as their own control, stratification of randomisation by 
GFR is deemed to be not necessary.
The follow-up period is 1 week, which is considered to be sufficient with empagliflozin have 
shown that the PD effect of empagliflozin only extends to about three days after the last dose
[c01678844-07].
This trial includes a control group.  The empagliflozin placebo control group is needed to 
control for what may be a small additive effect of empagliflozin when added onto ramipril
treatment in reducing GFR.  This control group will also provide control for the safety data 
that will be collected in this study.  All patients will continue to take their insulin therapy, 
which can be adjusted per Investigator guidance throughout the conduct of the trial and 
therefore, optimized care will be maintained.
The trial contains a comparator group which will include normofiltering patients (GFR = 60-
134 ml/min/1.73m2).   In this group of patients, it is expected that renal haemodynamic 
function (and sodium handling) with monotherapy (SGLT-2 or ACE inhibition) or 
combination therapy with the 2 agents will remain largely unchanged.  In contrast, it is 
expected that in the group with renal hyperfiltration significant effects on the renal 
haemodynamic parameters will be exhibited. Similarly, between group differences may be 
expected for BP and systemic vascular measures. As a result, it is important to include this 
control group so that it can be determined if the effects seen in patients with renal 
hyperfiltration are due to the neurohormonal and/or tubular hypothesis.
3.3
SELECTION OF TRIAL POPULATION
It is planned that approximately 150 patients will be screened to ensure the randomisation of 
approximately 74 patients.  In order to adhere to the proposed sample size and ensure that an 


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adequate number of patients with hyperfiltration are entered, no more than 40 normofilterer
patients (approximately 30 patients with T1D and approximately 10 patients who have T2D 
or are non-diabetic, obese individuals) will be entered based on GFR assessment at visit 4. As 
a result, screening for the study will continue until the required numbers of hyperfilterer
patients based on GFR at visit 4, have been randomised to trial treatment.
Re-screening:
Re-screening of the same patient is allowed after discussion with sponsor.  If a patient is re-
screened, the patient should be declared a screening failure in the eCRF and IRT with their 
original patient number.  Upon re-screening, the next available (i.e. new) patient number 
should be selected from electronic data capture (eDC) system.  The patient must be re-
consented using the current, approved version of the informed consent form.  
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
This study will be performed in adult patients with obesity, T2D, or T1D, who are on insulin 
pump therapy (continuous subcutaneous insulin infusion or CSII) or MDI treatment.  Patient 
eligibility will be assessed based upon a complete medical history including a physical 
examination and clinical laboratory tests.  
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
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 patients diagnosed with T1D at least 6 months prior to informed consent
or T2D or non-diabetic obese patients 
3. T1D patients must use and be willing, based on the Investigator’s judgement, to continue 
throughout the duration of the trial, either:

MDI’s of insulin consisting of any type of subcutaneous insulin (and be willing to 
continue on MDI therapy during the course of the study) OR

CSII of any insulin type, with at least 3 months experience of using CSII prior to Visit 
1
4. For patients with T1D or T2D, HbA1c of 6.5% to 11% at screening (Visit 1) measured by 
the central laboratory at Visit 1 (screening)


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5. Based on the Investigator’s judgment patient with T1D 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 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

established “sick day” management regimen
6. Age ≥18 years at Visit 1
7. BMI of ≥ 18.5 kg/m2
8. eGFR ≥ 60 ml/min/1.73m2 as calculated by the CKD-EPI formula, based on creatinine 
measured by the central laboratory at Visit 1
9. Average BP > 90/60 mmHg and ≤ 140/90 mmHg 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 
informed consent form 
*Women of child-bearing potential are defined as 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. 
hysterectomy, bilateral oophorectomy or bilateral salpingectomy)
3.3.3
Exclusion criteria
1. For patients with T1D, treatment with an antihyperglycaemic agent (e.g. metformin, 
alpha-glucosidase inhibitors, pramlintide, glucagon-like peptide receptor agonist, etc.) 
within 3 months prior to Visit 1 or any history of clinically relevant hypersensitivity 
according to Investigator’s judgment
2. Treatment with an SGLT-2i within 30 days of Visit 1
3. Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that 
required hospitalisation or hypoglycaemia-related treatment by an emergency physician 
or paramedic within 3 months prior to Visit 1
4. Hypoglycaemia unawareness based on Investigator judgement or frequent episodes of 
unexplained hypoglycaemia (2 or more unexplained episodes within 3 months prior to 
Visit 1)


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5. Occurrence of DKA within 3 months prior to Visit 1 and until Visit 3
6. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or
transient ischemic attack within 3 months prior to Visit 1
7. Diagnosis of severe gastroparesis (based on Investigator’s judgement).
8. Diagnosis of brittle diabetes based on Investigator judgement
9. Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), 
aspartate transaminase (AST), or alkaline phosphatase (AP) above 3 x upper limit of 
normal (ULN) at Visit 1 as measured by the central laboratory
10. Requires the ongoing use of any concomitant medication known to interfere with the 
RAAS activity and/or renal function based on investigator judgement.  Examples of 
restricted drug classes include ACEi, ARBs, aldosterone antagonists or renin inhibitors
11. Any contraindication to Altace® (ramipril) per local product monograph including the 
following:

History of angioedema

History of haemodynamically relevant bilateral renal artery stenosis or unilateral renal 
artery stenosis in a single kidney

History of hypotension or haemodynamically unstable states 

History of hypersensitivity reaction to ramipril or to any other ACEi, or to any 
ingredient in the ramipril formulation
12. History of organ transplant, including pancreas, pancreatic islet cells or renal transplant
13. Surgical treatment for weight-loss or aggressive diet regimen leading to unstable body 
weight (based on Investigator’s judgement) 3 months prior to Visit 1. For patients with 
T1D, use of anti-obesity drugs within 3 months prior to visit 1
14. 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
15. Change in dose of thyroid hormones within 6 weeks prior to Visit 1 or planned change or 
initiation of such therapy at Visit 1
16. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g., 
malaria, babesiosis, haemolytic anaemia) at Visit 1
17. Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial
18. Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial 
participation based on Investigator’s judgement
19. Intake of an investigational drug in another trial within 30 days prior to Visit 1


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20. Medical history of cancer or treatment for cancer five years prior to screening (Visit 1) 
with the exception of fully treated basal cell carcinoma
21. Patient not able to understand and comply with study requirements, based on 
Investigator’s judgment
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, patients who might be at higher risk of developing 
urinary, genital or mycotic infections, patients with chronic viral infections, etc.)
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
Patients who discontinue treatment after randomisation will be considered as “early 
discontinuations” and the reason for premature discontinuation must be recorded in the 
Electronic Case Report Form (eCRFs). The data will be included in the trial database and will 
be reported. 
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision

The patient needs to take a forbidden concomitant therapy (as listed in Section 3.3.3 and 
Section 4.2)

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy)

The patient experiences severe hypoglycaemia (for further details see Section 5.3.5.2) or 
repeated hypoglycaemic episodes or DKA that, in the Investigator’s opinion, may put the 
patient at risk with continued participation
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal (e.g. AEs) must be recorded in the (e)CRF. These 
data will be included in the trial database and reported.
If a patient becomes pregnant during the trial the investigational drug(s) will be stopped, the 
patient will be discontinued from the trial and the patient will be followed up until birth or 
otherwise termination of the pregnancy.
Patients who drop out prior to randomisation (Visit 8) will be considered a screening failure. 
They have to be recorded as screening failure in eCRFs.
3.3.4.2
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site


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2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the 
trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The study medication will be provided by Boehringer Ingelheim.  Insulin therapy is not 
considered to be part of the clinical trial supplies and therefore will not be provided by 
sponsor.
4.1.1
Identity of BI investigational product(s) and comparator product(s)
The characteristics of the test products are as shown below. 
Substance
Empagliflozin (Jardiance®)
Pharmaceutical Form
Tablet
Source
Boehringer Ingelheim
Unit Strength
25 mg
Route of administration
Oral, once daily
Substance
Placebo matching empagliflozin 25 mg
Pharmaceutical Form
Tablet
Source
Boehringer Ingelheim
Unit Strength
-
Route of administration
Oral, once daily
Substance
ramipril (Altace®)
Pharmaceutical Form
Capsule
Source
 or 
 
(commercial supply)
Unit Strength
5 mg
Route of administration
Oral, once daily during run-in.  May be dosed 
twice daily during randomised treatment as 
prescribed by the Investigator
Substance
ramipril (Altace®)
Pharmaceutical Form
Capsule
Source
or 
(commercial supply)
Unit Strength
10 mg
Route of administration
Oral, once daily
Substance
ramipril (Altace®)
Pharmaceutical Form
Capsule
Source
 or 
 
(commercial supply)
Unit Strength
1.25 mg
Route of administration
Oral, once or twice daily, as prescribed by 
the Investigator


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4.1.2
Method of assigning patients to treatment groups
During Visit 8 and after the patient’s eligibility has been confirmed based on the inclusion 
and exclusion criteria outline in Section 3.3.2 and Section 3.3.3, the treatment will be 
assigned via Interactive Response Technology (IRT). To facilitate the use of the IRT, the 
Investigator will receive all necessary instructions.
Patients will be randomly assigned to either Sequence A (25 mg empagliflozin followed by a 
4 week wash-out period followed by matching placebo during period 2 dosing) or Sequence
B (matching placebo followed by a 4 week wash-out period followed by 25 mg empagliflozin
during period 2 dosing) in a 1:1 balanced ratio. Randomisation will not be stratified 
according to GFR.  For further details please refer to Section 7.5.    
The assigned medication number will be entered in the eCRF, and the corresponding 
medication kit should be given to the patient. Using this procedure, relevant parties will be 
blinded to the treatment group assignment.
4.1.3
Selection of doses in the trial
Ramipril treatment should be initiated at 5 mg q.d. and then titrated to 10 mg q.d. after one 
week.  The 10 mg q.d. dose is the targeted dose.  A lower dose ramipril (1.25 mg) will also be 
available if patients are not able to tolerate either the 10 mg or 5 mg ramipril dose.  At the 
discretion of the Investigator, the patient may be prescribed a lower dose of ramipril if it is 
determined that the patient is unable to tolerate their current dose.  Patients may take a lower 
dose including:
7.5 mg q.d.
5 mg q.d.
2.5 mg b.i.d.
2.5 mg q.d.
1.25 mg b.i.d.
1.25 mg q.d.
It is preferred that the dose of ramipril prescribed at the start of period 2 dosing is either the 
same dose used at the start of period 1 dosing or the maximum tolerated dose for ramipril.  
For example, if a patient starts period 1 dosing at 10 mg ramipril but is dose reduced to 5 mg 
q.d., 1 week into period 1 dosing, the patient should start period 2 dosing on the 10 mg 
ramipril dose or on their maximum tolerated dose of ramipril during wash-out.  In this case, 
the up-titration of the ramipril dose should be done during the wash-out period.  Lower doses
of ramipril may be ordered through the IRT system.
Empagliflozin (25 mg) or matching placebo will be administered after randomisation during 
period 1 and period 2 dosing only. This dose was selected based on results from the previous 
trial that was conducted in patients with renal hyperfiltration [P13-16965].
4.1.4
Drug assignment and administration of doses for each patient
The treatments to be evaluated are outlined in Table 4.1.4:1 below.  All medication kits are to 
be ordered through the IRT.  The open-label run-in period includes a dose titration from 5 mg 
ramipril to 10 mg ramipril after one week of treatment.  After dose titration, all patients 
should remain on 10 mg ramipril for the duration of the study unless it is determined that the 


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patient is unable to tolerate the 10 mg dose.  Patients who qualify to be randomised will be 
assigned to one of two treatment sequences through IRT:

Sequence A:  25 mg empagliflozin in period 1 dosing followed a 4 week wash-out period 
followed by matching placebo in period 2 dosing

Sequence B:  matching placebo in period 1 dosing followed by a 4 week wash-out period 
followed 25 mg empagliflozin in period 2 dosing
Empagliflozin will be dispensed in a double-blind manner.  During period 1 and 2 dosing and
in the wash-out phase between each doing period, the patients will continue to take ramipril 
in an open label fashion.
Table 4.1.4:1 Oral administration of study medications per dose group 
Study 
Period
Ramipril 
5 mg
Ramipril 
10 mg
Empagliflozin 
25 mg
Matching placebo to 
empagliflozin
Sequence 
A
Run-in
X
Run-in
X*
Period 1
X*
X
Wash-out
X*
Period 2
X*
X
Sequence 
B
Run-in
X
Run-in
X*
Period 1
X*
X
Wash-out
X*
Period 2
X*
X
*patients may take a lower dose of ramipril at Investigator’s discretion (c.f. Section 4.1.3)
The 5 mg ramipril run-in medication will be dispensed by the Investigator or designee at visit 
4a.  The first administration of the ramipril medication should occur in the clinic under the 
supervision of the investigator or delegated site staff.  The date and time of medication intake 
will be recorded in the patient diary.
The ramipril and empagliflozin / placebo medication to be taking during Period 1 dosing will 
be dispensed by the Investigator or designee at the end of visit 8 and the patient will be 
instructed to take their first dose of study medication in the morning of study day 1 (i.e. the 
following day).  The date and time of medication intake will be recorded in the patient diary.
Patients should be instructed to take all study medication with water, with or without food.  
Ramipril (if dosed q.d.) and empagliflozin/ placebo should be taken once daily in the morning 
between 07:00 and 11:00, except when the patient has a clinic visit since the study 
medications will be administered in the clinic.  To ensure a dose interval of approximately 24 
hours, the medications should be taken at the same time every day. If a dose is missed by 


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more than 12 hours, that dose should be skipped and the next dose should be taken as 
scheduled.  
If a patient is prescribed a lower dose of ramipril that required twice daily dosing, then the 
ramipril medication should be taken in the morning (between 07:00 and 11:00) and in the 
evening (between 19:00 and 23:00).  Patients should try to take their study medications at the 
same time each day except on days when the patient is scheduled to come into the clinic, as 
the study medications will be administered in the clinic.  If a dose is missed by more than 6 
hours, that dose should be skipped and the next dose should be taken as scheduled.
Patients are not permitted to take more than 10 mg of ramipril or take double doses or a lower 
dose of empagliflozin/placebo.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, the Investigator and everyone involved in trial conduct or analysis or with any other 
interest in this double-blind trial will remain blinded with regard to the randomised 
empagliflozin or matching placebo treatment assignments until after database lock.  The 
randomisation code will be kept secret by the Clinical Trial Support Group up to database 
lock.  
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report 7 / 15 day reports, it may be necessary for a representative 
from BI’s pharmacovigilance group to access the randomisation code for individual patients 
during study conduct. In such cases, access to the code will only be permitted by authorised 
pharmacovigilance representatives. Access to the code will be via an IRT system.
4.1.6
Packaging, labelling, and re-supply
Study medication (ramipril, empagliflozin, empagliflozin matching-placebo) will be provided 
by the
 
. The study medication will be dispensed as indicated in the 
Flow Chart.  The study medication will consist of containers labelled with the trial 
identification and medication kit number.  Each container will contain an appropriate number 
of empagliflozin tablets (or placebo) or ramipril capsules with some reserve for dosing until 
the next scheduled visit. 
Supply and re-supply will be managed by an IRT system.
For details of packaging and the description of the label, refer to the ISF.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the CML (as provided in 
the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The Investigator and/or Pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the Sponsor when the following requirements are 
fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB) / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the PI,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the PI
The Investigator and/or Pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor, the Investigator / Pharmacist / investigational drug storage manager must verify that 
all unused or partially used drug supplies have been returned by the clinical trial patient and 
that no remaining supplies are in the Investigator’s possession.
4.1.8.1
Patient treatment compliance
Patients will be asked to return all trial medication kits (with or without any remaining 
tablets) with them to each trial visit. The tablets will be counted by the Investigator or a 
qualified designee and compliance will be calculated according to the formula:
Compliance (%) =
Number of tablets actually taken since last tablet count
x 100%
Number of tablets which should have been taken in the same period


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Compliance during the open-label run-in period must be between 80% and 120 %.  If 
complinace is outside of this range, the patient should be carefully interviewed and, if 
necessary, re-informed about the purpose and the conduct of the trial.  Unreliable patients 
should not be randomised at the discretion of the Investigator.
Compliance during the randomised treatment period should also be between 80% and 120%.  
Patients who are non-compliant according to this definition will be treated as protocol 
violators.  The significance of the protocol violations will be determined individually for the 
purposes of the per-protocol analysis.
Patients who are not compliant with their medication should again be carefully interviewed 
and again informed about the purpose and the conduct of the trial.  This dicsussion should be 
documented.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
Details of all concomitant therapy during the clinical trial will be recorded on the appropriate 
pages of the eCRF.
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
There are no rescue medications in this trial. Anti-hyperglycaemic therapy including insulin
will not be provided as part of the clinical trial supplies. 
Patients who are unable to tolerate (e.g. due to hypotensive side effect) the 10 mg dose of 
ramipril may be treated with lower doses of ramipril based on Investigator judgement (c.f. 
Section 4.1.3).  Any patient who experiences a severe allergic reaction (e.g. angioedema) 
should immediately stop taking ramipril.
During periods of stability, in case of hypoglycaemia (e.g. with measured glucose 
concentrations ≤ 3.9 mmol/L), patients should preferably ingest additional carbohydrate 
according to standard practice in the management of diabetes.  However a patient’s existing 
diabetic regimen should be adjusted any time for safety reasons if deemed necessary by the 
Investigator (e.g., in case of persisting hyperglycaemia or hypoglycaemia despite adequate 
carbohydrate intake).
Based on the mode of action of empagliflozin and the results of the previous trials in T1D 
(for further details see Section 1), at the start of Period 1 and Period 2 dosing, for T1D
patients with an HbA1c of < 8% at Visit 1, the Investigator is advised to reduce the patient’s 
total insulin dose by 10% to avoid hypoglycaemia.  For T1D patients with an HbA1c of ≥ 8% 
at Visit 1, Investigators are advised to adjust the patient’s total insulin dose based on need as 
assessed by frequent SBGM and close patient follow-up upon initiation of randomised study 
medication. In all cases, the actual reduction will be dependent upon individual glucose 
values.  Thereafter and until the end of the trial, further adjustments to insulin therapy may be 
implemented as necessary to avoid hypoglycaemia and hyperglycaemia to keep ensuring that, 
in the Investigator’s opinion, the patient is achieving the best standard of care in accordance 
with local guidelines. 


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Apart from the recommendation for an initial insulin reduction as mentioned above, at the 
start of randomised treatment, there will be no protocol-defined algorithm towards insulin 
adjustment in this trial.  However, the Sponsor will provide additional support to the 
Investigator with respect to insulin adjustment via training documentation that will be 
presented at Investigator Meetings and made available in the ISF.  Throughout the trial, 
adjustment needs to balance a patient’s individual risk for hypoglycaemia on the one hand 
and the risk for hyperglycaemia and DKA on the other hand with special caution at the 
beginning of Period 1 and Period 2 dosing, and in the wash-out and follow-up periods, when 
empagliflozin treatment is started and stopped respectively.  Any insulin dose change or 
adjustment must be based on laboratory tests or SBGM.  However, there are no blood glucose 
targets defined throughout this trial to allow the Investigator to follow local standard of care 
guidelines for the management of blood glucose.  Whenever possible, patients should keep to 
the same trademark and application device for their existing insulin with no intention to 
change this during the trial; for medical / safety reasons however (e.g. malfunction of a pump 
in a CSII patient), switches in mode of insulin delivery are permitted.  There should also be 
no planned major changes of the injection sites / areas.
In accordance with Section 3.3.2, the Investigator must ensure that the patient with T1D 
selected for the trial are capable of leading the management and adjustment of their insulin 
therapy when at home, including a ‘sick day’ management plan, and at the same time, can be 
relied upon to contact the Investigator for advice at the appropriate point in time.  Investigator 
oversight will also be an important element of the insulin adjustment process.
Special attention must be paid to the prevention of DKA.  Due to the mechanism of action, 
insulin-dependent (T1D and T2D) patients treated with empagliflozin are at risk to 
underestimate their need for insulin in case of blood sugar levels within their individual target 
range.  Insulin deficiency might lead to ketoacidosis which could be life-threatening if not 
recognised and appropriately treated.  All patients must be made aware of this risk and be 
instructed not to reduce their insulin intake below Investigator’s recommendations.  For 
further details see Section 2.3.
In addition to performing glucose monitoring, the frequency of which will be increased after 
starting the study medication (for further details see Section 5.3.2.1), in the same way as 
during routine clinical care, insulin-dependent patients with T1D or T2D will be reminded to 
determine ketones in case of any symptoms of DKA (e.g., nausea, vomiting, abdominal pain, 
etc. (see Section 5.3.2.2).  They will be instructed to do this irrespective of their glucose 
value in the event of DKA symptoms occurring.  A meter will be provided to the patient for 
this purpose. Patients will be also reminded about the interpretation of ketone values 
measured via the meter, and on appropriate action to take in the event of increased ketone 
levels (see Section 5.3.2.2).  Ketones should also be determined in case of repeatedly elevated 
blood glucose levels (e.g. > 11.1 – 13.3 mmol/L) which cannot be explained. Regular (e.g., 
once daily) measurements before breakfast are recommended during period 1 and period 2 
dosing and for 5 days after stopping the empagliflozin / placebo treatment.  In case of a 
suspected DKA, the Investigator should ensure that appropriate tests are performed at the 
earliest opportunity according to local guidelines, such as a blood gas test (i.e., pH, 
bicarbonate; the results will be collected on the relevant page of the eCRF) and that the 
patient is appropriately treated (i.e., hospitalized or referred to emergency treatment) 
according to the local treatment guidelines.    


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Other concomitant therapies should be kept as stable as possible over the course of the trial 
but could be changed in case of medical need.  New anti-diabetic therapy should not be 
initiated during the Follow-up period.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Any treatment that is known to interfere with RAAS activity and/or renal function is strictly 
prohibited except for the ramipril study medication provided through the trial.  Such 
medications include ACEi, ARBs, aldosterone antagonists and renin inhibitors or any other 
medication / drug class per Investigator judgement which may interfere with RAAS activity 
and/or renal function.
In patients with T1D, use of antihyperglycaemic drugs (e.g. metformin, other SGLT2i’s, 
alpha-glucosidase inhibitors, pramlintide, etc.) other than insulin and the provided study 
medications should not be used during the trial including the follow-up period.
Use of other SGLT2i-s will be prohibited during the trial including the follow-up period.
Concomitant use of ramipril and extracorporeal treatments leading to contact of blood with 
negatively charged surfaces must be avoided as this may lead to anaphylactoid reactions.  If 
such a treatment is required (e.g. dialysis or haemofiltration), the patient should be 
discontinued from the trial.
Treatment with anti-obesity drugs in patients with T1D or systemic steroids will be 
prohibited due to their influence on glucose metabolism.  However, short-term use (i.e. ≤ 3 
days duration) of systemic steroids, if deemed appropriate by the Investigator will be 
permitted as well as therapy with non-systemic steroids such as inhaled or local steroids.  For 
patients taking thyroid hormones, any changes in the dose should be avoided.  If a dose 
change does occur, then they should be recorded in the source documents and in the eCRF.
4.2.2.2
Restrictions on diet and life style
At the screening visit, patients will receive diet and exercise counselling by the Investigator
or qualified site personnel. The counselling will be based on local diet recommendations for 
the patients with T1D in consideration with each patient’s possible concomitant illnesses.  
Site specific tools may be used to help patients with diet and lifestyle / exercise counselling.  
The patients will be reminded to follow the recommended diet and exercise plan during the 
study.  Patients are also requested to adhere to a specific sodium rich (preferably > 140 
mmol/day) and moderate-protein (<1.5 g/kg/day) diet only during the 7 days preceding the 
start of the renal physiology laboratory assessments (7 days before study days -42, -1, 28 and 
84).  Details of this specific diet will be given to patients at Visit 1 and patients will be 
reminded to re-start this diet via a phone call approximately 7 days prior to study Days -42, -
1, 28 and 84).
Patients should not participate in strenuous physical activity that requires significant changes 
to their diet and insulin during the run-in and treatment periods.  Extreme diets (e.g. 
ketogenic diets) should be avoided.


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Women of child-bearing potential must use a highly effective method of birth control (in 
accordance with the trial exclusion criteria cf. Section 3.3.3) throughout the duration of the 
study, including the follow-up period.
Patients must not take any other investigational drug within 30 days before Visit 1 until the 
last visit (Visit 16) of this trial.


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5.
VARIABLES AND THEIR ASSESSMENT 
5.1
TRIAL ENDPOINTS
None of the endpoints are a known safety issue.
5.1.1
Primary Endpoint(s)
The primary endpoint is GFR under euglycaemic conditions after 4 weeks of treatment with 
either empagliflozin added to ramipril or placebo added to ramipril.
5.1.2
Secondary Endpoint(s)
Filtration status (GFR < 120 mL/min/1.73m2; yes/no) after 4 weeks of treatment with either 
empagliflozin added to ramipril or placebo added to ramipril.


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5.2
ASSESSMENT OF EFFICACY
5.2.1
Haemodynamic measurements
For all experimental phases, blood glucose will be monitored routinely in obese (non-
diabetic) patients to ensure that plasma glucose is between 4 – 6 mmol/L.  In all diabetic 
patients and those obese patients with elevated blood sugar (i.e. > 6 mmol/L), blood glucose 
is maintained by a modified glucose clamp technique, as previously described [R10-6374]. In 
summary, a 16-gauge peripheral venous cannula is inserted into the left antecubital vein for 


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infusion of glucose and insulin and more distally, a second cannula is inserted for blood 
sampling. Blood glucose is measured every 10–15 min, and the insulin infusion is adjusted to 
maintain the desired glycaemic index. Experiments are performed in the same temperature 
controlled room and in a dark, quiet environment after 10 min of rest in the supine position. 
Renal and systemic vascular function assessments are performed at baseline (visit 4) and then 
repeated in an identical fashion at the end of each period dosing (visit 8, 11 and 15). 
Following arterial stiffness assessments (more details in Section 5.2.3), an intravenous line is 
inserted into the right arm and is connected to a syringe infusion pump.  In the first 31 
randomized patients in the trial, inulin and paraaminohippurate (PAH) was administeredafter 
collection of blood for inulin and PAH blank. A priming infusion containing 25% inulin (60 
mg/kg) and 20% PAH (8 mg/kg) is administered. Thereafter, inulin and PAH are infused 
continuously at a rate calculated to maintain their respective plasma concentrations constant 
at 20 and 1.5 mg/dl. After a 90-min equilibration period, blood is collected for inulin, PAH, 
and haematocrit. Blood is also collected as applicable every 30 mins for inulin, PAH and 
haematocrit measurements. GFR and ERPF are respectively estimated by steady-state 
infusion of inulin and PAH [R10-6364].
In the remaining patients entered into the trial, a bolus infusion of iohexol is administered 
approximately 2 hours prior to the infusion of 20% PAH (8 mg/kg) [R18-1807, R18-1808].  
PAH is infused continuously at a rate calculated to maintain a plasma concentration of 1.5 
mg/dl.  GFR and ERPF are estimated based on concentrations of iohexol and PAH based on 
blood sample collections at the following time points:
Time Point
Activity
0
Iohexol (pre-dose) plasma sample 
collection
Iohexol infusion
+120 min
PAH (pre-dose) sample collection
PAH infusion
Iohexol plasma sample collection
Haematocrit sample collection
+150 min
Iohexol plasma sample collection
Haematocrit sample collection
+180 min
Iohexol plasma sample collection
Haematocrit sample collection
+ 210 min
Iohexol plasma sample collection
PAH sample collection 
Haematocrit sample collection
+240 min
Iohexol plasma sample collection


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PAH sample collection
Haematocrit sample collection
5.2.2
Segmental tubular handling of sodium
Tubular sodium handling will be assessed using an established sodium and lithium clearance 
technique [R15-3481, R15-3480].  Approximately 12 hours prior to renal assessment visits 
(Visits 4, 8, 11 and 15); patients will be required to take 300 mg lithium orally.  During renal 
assessment visit, after euglycaemia equilibrium has been achieved, blood and urine samples 
for sodium, lithium and creatinine will be collected at 3 time-points. The estimated proximal 
fractional fluid re-absorption rate and the estimated absolute distal sodium delivery can be 
calculated based on the urinary lithium, sodium clearances, GFR and the lithium and sodium 
fractional excretion rates.  
5.2.3
Arterial stiffness and sympathetic nervous system (SNS) measurements
Augmentation index (AIx) for the radial and carotid arteries as well as a derived aortic AIx 
and carotid, radial and femoral pulse wave velocities will be measured for assessment of 
arterial stiffness when feasible using a SphygmoCor® System, and necessary software or a 
similar instrument based on previously published methodologies [R11-0072].  Such an 
instrument allows a non-invasive means of quantifying cardiac autonomic activity allowing 
assessment of sympathetic and parasympathetic autonomic function including variable heart 
rate which will be measured as part of the SNS assessments. The SphygmoCor® System 
provides a comprehensive assessment of the key cardiac parameters including central BP, 
arterial stiffness and autonomic function and calculates both time and frequency domain heart 
rate variability parameters, including the vagal index. The use of the SphygmoCor® System 
for assessment of arterial stiffness and endothelial function has been previously validated 
[R10-6380].
5.2.4
Blood pressure (BP) and pulse rate
5.2.4.1
Routine clinic visits
The initial reading of BP at screening (Visit 1) should be done in both arms. If the pressures 
differ by more than 10 mmHg (as in the presence of a subclavian steal syndrome), the arm 
with the higher pressure (systolic or if needed to decide, diastolic) should be used for 
subsequent measurements.
BP measurements should be performed on the same arm after the initial assessment and, if 
possible, by the same person. The same method and device must be used throughout the trial 
for a patient.
For routine vital sign assessments (not at visits 4, 8, 11 and 15), systolic and diastolic BP as 
well as pulse rate will be measured after 5 minutes of rest in the supine position. The BP 
measurement should be performed three times and all three measurements will be entered in 
the eCRF. The second and third BP measurements will be done respectively 2 minutes and 4 


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minutes after the initial measurement. The pulse rate measurement will be done during the 2nd
and 3rd BP measurement after a full minute count.
5.2.4.2
Renal study visits
BP and pulse rate measurements will be made using an automated Dinamap 
sphygmomanometer.  Measurements will be taken in the supine position during the renal 
study days (visit 4, 8, 11 and 15). An average of three measurements will be recorded and 
used to calculate renal haemodynamic parameters following the procedure outlined in section 
5.2.4.1.    BP measurements should be recorded to the nearest 2 mmHg only when measured 
with a manual sphygmomanometer; when digital devices are used, the value from the device 
should be rounded to the nearest 1 mmHg.
5.2.5
Weight and waist circumference
Weight measurements should always be done on the same scale for each patient.  In order to 
get comparable body weight values, it should be performed in the following way:

After the urine sampling (weigh after bladder voiding)

Shoes and coats/jacket should be removed

Pockets should be emptied of heavy objects (e.g. keys, coins, etc.)
Waist circumference measurements should be made around the patient’s bare midriff, after 
the patient exhales while standing without shoes and with both feed touching and arms 
hanging freely.  The measuring tape should be made of a material that is not easily stretched, 
such as fiberglass.  The tape should be placed perpendicular to the long axis of the body and 
horizontal to the floor and applied with sufficient tension to conform to the measurement 
surface.  
Waist circumference should be determined by measuring the midpoint between the lowest rib 
and the iliac crest.
5.2.6
Ambulatory blood pressure monitoring
The ABPM device will be programmed to measure BP every 20 minutes throughout the day 
and night. Patients should be advised not to move the arm during each BP measurement and 
will also be given instructions concerning interruption of measurement in case of malfunction 
of the device or repositioning of the cuff if it slips.
At each ABPM visit (Visits 3, 7, 10 and 14), patients are to come to the clinic and the 
following procedure will be performed.   

The ABPM monitor will be attached to the patient and checked to see if it is working 
properly prior to medication intake (except visit 3).  

Once it has been confirmed that the monitor is properly functioning, study medication 
will be administered followed by prompting of the monitor to take the Beginning of Test 
reading.  

Record the time the medication was administered and the time the monitor was prompted 
to take the Beginning of Test reading.  


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
The next day when the patient returns to the clinic, the monitor will be prompted to take a 
Conclusion of Test reading.  The device will then be removed and the time of the 
Conclusion of Test will be recorded.  This should be done preferably within 22-24 hours 
of starting monitor.  
After the removal of the monitor and prior to study medication intake, the patient will be 
allowed rest for 15 minutes and a seated BP measurement (trough BP) will be taken.  The 
patient will then be given study medication.  The time for each of the seated BP 
measurement, medication intake, and the beginning and conclusion of the 24 hours ABPM 
readings must be recorded.  
Further details on the procedure for BP measurement utilizing ABPM device can be found in 
the ISF.
5.2.7
Non-invasive cardiac output monitoring
Cardiac output, stroke volume and total peripheral resistance will be derived from stroke 
volume and heart rate that is measured using the Non-Invasive Cardiac Output Monitoring
(NICOM®) system (Cheetah Medical Inc.) under conditions of euglycaemia at visits 4, 8, 11 
and 15. The NICOM® monitoring system is based on Bioreactance® technology [R15-3482].  
Four sensor pads will be applied above and below heart on the chest.  Each sensor pad 
contains an outer transmitting sensor and an inner receiving sensor.  The NICOM® monitor 
induces a 75KHz AC current to the thorax via the outer sensors and receives the voltage via 
the inner sensors.  The sensors can detect a time delay or phase shift between the induced 
current and the received voltage.  Stroke volume is derived based on consecutive 
measurements of the phase shift.
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A complete physical examination will be performed by the Investigator or designated site 
personnel at the time-points indicated in the Flow Chart.  Documentation of, and findings 
from the physical examination, must be part of the source documents available at the site.
5.3.2
Home monitoring
5.3.2.1
Self Blood Glucose Monitoring (SBGM)
From the beginning of the trial (Visit 1) until the end of the follow-up period (Visit 16), all 
patients with diabetes (T1D or T2D) will be provided with SBGM equipment (i.e., a glucose 
monitoring device / meter) and supplies for use at home and at the site during the study for 
SBGM.  Instructions on the proper use of the SBGM equipment will be provided by the site 
staff.  The patient will be asked to record the results of the SBGM test on a log that will be 
included in the patient’s source document file.  Only in the case of linked AEs or of 
hypoglycaemia, will glucose levels from the SBGM be documented in the eCRF.  Obese 
patients who do not have diabetes are not required to monitor blood glucose unless deemed 
necessary by the investigator.


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Patients with T2D, SBGM testing should be performed at least once per day as a minimum or 
more frequently as recommended by the Investigator or at any time when the patient is 
experiencing symptoms of hypo- or hyperglycaemia.  
For patients with T1D, SBGM testing should be performed 4 times a day as a minimum (i.e. 
at least before breakfast, lunch, dinner and at bedtime); furthermore, for 5 days after 
randomisation to empagliflozin / placebo, SBGM testing frequency should be increased to 8-
10 times a day and include at least one overnight measurement.  Additional tests should be 
done as recommended by the Investigator or at any time the patient is symptomatic, i.e. 
experiences signs/symptoms of hyper- or hypoglycaemia.  In patients prone to nocturnal 
hypoglycaemic events, a bedtime snack consisting of long-acting carbohydrates should be 
considered. Alternatively, minimum glucose levels of e.g. > 6.1 – 7.2 mmol/L (>110 – 130 
mg/dL) should be targeted at bedtime to avoid nocturnal hypoglycaemia.  The sponsor will 
also provide guidance on this topic via documentation in the ISF.  
For patients with diabetes, if, after an overnight fast, a SBGM test result reveals blood 
glucose of > 11.1 - 13.3 mmol/L (200 – 240 mg/dL) or < 3.9 mmol/L (70 mg/dL), the patient 
should be asked to contact the site for advice.  The Investigator should then instruct the 
patient on appropriate measures in order to adequately control their hyperglycaemia or 
hypoglycaemia.  All insulin treatment decisions should be based on blood glucose values 
measured using SBGM or based on laboratory values obtained through the central laboratory 
(or, if applicable, the local laboratory).  
The same SBGM system will be supplied to all patients with diabetes and must be used by 
the patient throughout the study.  In accordance with Section 3.3.2, the Investigator should 
carefully select patients for the study in terms of their ability to comply with the SBGM 
requirements.  Patients not adhering to the SBGM instructions given by the Investigator
should be re-trained at the earliest possible opportunity.
5.3.2.2
Ketone monitoring
Patients with T1D or patients who are only using insulin for management of diabetes will be 
provided with an electronic device to determine their ketone concentration (i.e. a blood 
glucose monitoring device/meter that is also capable of measuring blood ketones).  Patients 
with T2D, who are managed with oral anti-hyperglycaemic agents only, or obese patients, are 
not required to monitor their ketones unless requested to do so by the investigator.
Patients should measure their ketones at least one daily, ideally after fasting for at least 6 
hours, throughout the Period 1 and Period 2 dosing, including for 5 days after empagliflozin / 
placebo treatment has been stopped.  Patients should be reminded to test their ketones in case 
of any symptoms of DKA, e.g. nausea, vomiting, and abdominal pain.  Patients must be 
reminded about the signs and symptoms of DKA, on the interpretation of ketone values 
measured via the meter, and on appropriate action to take in the event of increased ketone 
levels (see below).  In the same way as during routine clinical care, patients should also be 
reminded to test for ketones in case of repeatedly elevated blood glucose levels (e.g. >11.1 
mmol/L (> 200 mg/dL)) which cannot be explained.  
In the event of increased ketones, patients should either follow the rules given by their 
Investigator (e.g. increased fluid intake and/or insulin bolus or temporarily discontinue study 
drug) or contact their trial site.  Blood glucose and ketone levels should be checked every 1-2 


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hours until they are back in a range considered to be normal.  Patients should be instructed to 
immediately refer themselves to hospital and/or the Investigator, or to contact an emergency 
physician in case of a blood ketone concentration > 1.5 mmol/L (as indicated in the meter 
manual).  In case of a suspected DKA a blood gas test (pH, bicarbonate) should be performed 
locally at the earliest opportunity.  The results will be collected on the relevant page of the 
eCRF.
In accordance with Section 3.3.2, Investigator’s should carefully select patients for the study 
in terms of their ability to comply with ketone measurement requirements.  Patients not 
adhering to the instructions given by the Investigator should be retrained at the earliest 
possible opportunity.
5.3.2.3
Blood Pressure
Patients will be provided with a personal BP monitor at visit 4a for use at home.  Instructions 
on the proper use of the equipment will be provided by the site staff. Only in the case of 
linked AEs, will the BP readings be documented in the eCRF.
Routinely, BP monitoring should be performed twice a day (i.e. morning and at bedtime).  
Additional tests should be done as recommended by the Investigator or at any time the patient 
is symptomatic, i.e. feels light-headed or experiences postural hypotension.  
If BP values repeatedly fall below 90/60 mmHg, the patient should contact the site 
immediately.  
5.3.3
Safety laboratory parameters
All safety and efficacy laboratory samples will be collected according to the summary of 
assessments in Table 5.3.3:1 and Table 5.3.3:2 below.  The Flow chart specifies which visits 
should be conducted when the patient is fasting.  Laboratory samples should be collected 
before the administration of study medication as described in the Flow Chart. Patients should 
continue to take their prescribed medications as instructed by the prescribing physician.
The analysis of the safety laboratory parameters will be performed by a central laboratory.  
The respective reference ranges and details about sample handling and shipment will be 
provided in the laboratory manual in the ISF.


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Table 5.3.3: 1
Safety laboratory parameters 
Haematology:

Haematocrit

Haemoglobin
- Reticulocyte Count (if haemoglobin is outside normal range)

Red Blood Cells (RBC) / Erythrocytes

White Blood Cells (WBC) / Leukocytes

Platelet Count / Thrombocytes

Differential Automatic (relative and absolute count): 
Neutrophils, Eosinophils, Basophils, Monocytes,  Lymphocytes
Table 5.3.3:1
Safety laboratory parameters, continued
Clinical chemistry:

Albumin 

Alkaline phosphatase 

Gamma-glutamyl transferase (γ-GT, reflex test triggered by elevated AP on 
two sequential measures)

ALT (alanine aminotransaminase, SGPT)

AST (aspartate aminotransaminase, SGOT) 

Beta-hydroxybutyrate (BHB)1

Bicarbonate

Bilirubin total (fractionated if elevated)

Calcium 

Chloride 

Creatinine 

Creatine kinase (CK)

hs troponin T (reflex tests if CK is elevated)

C-peptide2 (performed at screening only in T1D patients only)

Lactate dehydrogenase 

Lipase

Magnesium 

Phosphate 

Potassium 

Protein total 

Sodium

Blood urea nitrogen

Uric acid
Lipids:

Cholesterol (total)

HDL cholesterol 

LDL cholesterol 

Triglycerides


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Other assessments at selected visits:

Thyroid stimulating hormone2 (TSH) (screening only)

Glycated haemoglobin (HbA1c)

Fasting plasma glucose (FPG)

Human Chorionic Gonadotropin (hCG)3
Table 5.3.3:1
Safety laboratory parameters, continued
Urinalysis:
Dipstick (A):
Immediate site assessment for leukocyte and/or nitrite4
Routine urinalysis (B):

Glucose

Ketone 

Specific Gravity

Blood

Urine pH 

Protein 

Nitrite

Leukocyte/Leukocyte esterase
Quantitative (C):

Albumin2

Creatinine2

Alpha-1 microglobulin

BHB1
24 hour urine collection:

Sodium, glucose, BHB1, urea and creatinine 
1. BHB to be tested at visits 1, 4, 8, 11, 12 and 15. At visits 4, 8, 11, and 15 blood and 
urine samples are to be collected within 30 minutes of starting the inulin or iohexol 
and PAH infusion and also between 1.5 and 2 hours after the study medication has 
been administered.  
2. Visit 1 safety lab tests will include haematology, chemistry, C-peptide (only in T1D 
patients) TSH (only measured at visit 1) and routine urinalysis B.  Urine albumin and 
creatinine to be measured at visit 1 including calculation of the albumin/creatinine 
ratio.
3. Pregnancy testing (serum) will be performed in female patients of child bearing 
potential at specified visits in the flow chart. Additional tests may be done if locally 
required and per Investigator judgement.
4. A mid-stream urine sample must be sent for culture upon a positive leukocyte and/or 
nitrite assessment based on dipstick at the site or upon Investigator suspicion of a 
UTI.


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An eGFR will be derived from serum creatinine values at visit 1 and visit 8 based on the 
CKD-EPI formula which is considered to be more accurate in the normal range than the 
Modification of Diet in Renal disease formula.  The CKD-EPI formula will be defined in the 
central laboratory documentation due to the regional / racial variations in the formula that is 
applied. 
The following renal analysis will be completed at visit 4, 8, 11 and 15 (under euglycemic 
conditions).  Inulin and PAH analysis will be performed by the local laboratory.  
Table 5.3.3: 2
Renal analysis
Renal panel (plasma samples):

cGMP 

Nitric oxide

Angiotensin II (RAAS mediator)

Angiotensinogen (RAAS mediator)

Aldosterone (RAAS mediator)

Plasma renin activity (RAAS mediator)

Plasma renin concentration (RAAS mediator)

Inulin or Iohexol

Lithium

Paraaminohippurate (PAH)

8-hydroxydeoxyguanosine

8-isoprostane
Quantitative urinalysis (C):

cGMP 

Nitric oxide

cAMP

Lithium

8-hydroxydeoxyguanosine

8-isoprostane
5.3.3.1
Follow-up on suspicion for urinary tract infections
Patients having a history of chronic/recurrent UTI or genital infection or an acute episode of 
UTI or genital tract infection at screening will be identified and this condition must be 
documented as a medical history or as a baseline condition in the eCRF, respectively.  
Throughout the trial, patients should be closely observed for symptoms of UTI or genital 
infection.  In case these symptoms occur, symptomatic relief and antibiotics should be 
provided as appropriate.  
For documentation of acute UTI during the trial conduct, the following measures have to be 
taken:


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
In any case of suspected UTI (symptomatic or asymptomatic) a urine culture sample has 
to be taken and sent to the central laboratory for confirmation of the diagnosis and to 
obtain an antibiogram

To be able to identify asymptomatic UTIs immediately, a dipstick test (leukocyte esterase 
[for WBC] and nitrite) will be performed at the site at the time-points indicated in the 
Flow Chart.  In case of a positive result at the site, a urine culture must be obtained and 
sent to the central laboratory for confirmation of the diagnosis and to obtain an 
antibiogram.
5.3.4
Electrocardiogram
Printed paper traces from 12 lead ECGs (I, II, III,aVR,aVL,aVF,V1-V6) will be collected at 
baseline and at the end of the trial for all patients. In the event of any cardiac symptoms (i.e. 
suspicion of heart rhythm disorders or cardiac ischemia), an additional ECG will be recorded. 
All ECGs will be evaluated, (signed, dated and commented upon) by the treating 
physician/Investigator and stored locally. Any clinically relevant changes in the ECG will be 
reported as AEs and followed up and/or treated locally until normal or stable condition.
5.3.5
Other safety parameters
5.3.5.1
Assessment of hypoglycaemia rate
Hypoglycaemia rates will be assessed based on AE data, which in turn rely on the criteria for 
hypoglycaemic events (see Section 5.3.5.2 below).  Glucose values used within the criteria 
for hypoglycaemic events will originate in the SBGM device and from the central laboratory 
measurements.  Glucose values originating from the SBGM device will subsequently be 
entered into the patient diary.
5.3.5.2
Criteria for hypoglycaemic events
Every episode of plasma glucose below or equal to 3.9 mmol/l (70 mg/dl) should be 
documented with the respective time and date of occurrence. This includes any 
hypoglycaemia with glucose values <3.0 mmol/l (<54 mg/dl) and all symptomatic and severe 
hypoglycaemias. 
For the analysis, all hypoglycaemias will be classified according to the following criteria:

Asymptomatic hypoglycaemia: Event not accompanied by typical symptoms of 
hypoglycaemia but with a measured plasma glucose concentration ≤3.9 mmol/l (≤70 
mg/dl)

Documented symptomatic hypoglycaemia with glucose concentration ≥3.0 mmol/l and 
≤3.9 mmol/l (≥54 mg/dl and ≤70 mg/dl): Event accompanied by typical symptoms of 
hypoglycaemia 

Documented symptomatic hypoglycaemia with glucose concentration <3.0 mmol/l (<54 
mg/dl): Event accompanied by typical symptoms of hypoglycaemia but no need for 
external assistance


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
Severe hypoglycaemic episode: Event requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other resuscitative actions.  Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event 
was induced by a low plasma glucose concentration [R14-0982].
If a patient is provided with an emergency glucagon injection device as part of their local, 
routine T1D care, it is advisable for the patient to carry this throughout the trial.  
5.3.5.3
Criteria for diabetic ketoacidosis
Refer to Section 5.3.6.1.
5.3.6
Assessment of Adverse Events
5.3.6.1
Definitions of AEs 
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorisation or from occupational 
exposure. Conditions of use outside the marketing authorization include off-label use, 
overdose, misuse, abuse and medication errors.
Serious adverse event
A SAE is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgement which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.


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Medical and scientific judgment should be exercised in deciding whether other situations
should be considered serious reactions, such as important medical events that might not be
immediately life threatening or result in death or hospitalisation but might jeopardise the
patient or might require intervention to prevent one of the other outcomes listed above.
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or
development of dependency or abuse. Any suspected transmission via a medicinal product of
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above and in Section 5.3.7.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
Patients with AESIs need to be followed up appropriately, regardless of the origin of the 
laboratory data (e.g., central or local lab, etc.).  The Investigator should consider which, if 
any, concomitant therapies should not be taken during evaluation.  Discontinued treatments 
can be reintroduced per Investigator discretion. 
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters after 
run-in (Visit 4): 

an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

an isolated elevation of ALT and/or AST ≥5 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided via the eDC
system.


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In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Decreased renal function
Decreased renal function is defined by a creatinine value showing a ≥2 fold increase from 
baseline and is above the ULN.  
For the AESI “decreased renal function” the Investigator shall collect an unscheduled 
laboratory sample for creatinine as soon as possible and initiate follow-up laboratory tests of 
creatinine according to medical judgement.
Diabetic ketoacidosis
DKA is defined by the diagnostic criteria in Table 5.3.6.1:1 below, and as defined by the 
ADA [R14-5435].
Investigators should note that not all criteria in the table below need to apply for the diagnosis 
of DKA, and clinical judgment should also be taken into consideration.  Due to its 
mechanism of action, empagliflozin may potentially modify the clinical presentation of DKA 
which may occur at lower plasma glucose levels than stated in the table below (see Section
1.2.3.2 and Section 2.3 for further details).
Table 5.3.6.1: 1
Diagnostic Criteria for DKA
DKA
Mild
Moderate
Severe
Plasma glucose (mg/dL / mmol/L)
>250 / 13.9 
>250 / 13.9
>250 / 13.9
Arterial pH
7.25 – 7.30
7.00 – 7.24
< 7.00
Serum bicarbonate (mEq/L)
15 - 18
10 to < 15
< 10
Urine ketones*
Positive
Positive
Positive
Serum ketones*
Positive
Positive
Positive
Effective serum osmolality (mOsm/kg)**
Variable
Variable
Variable
Anion gap***
>10
>12
>12
Mental status
Alert
Alert / drowsy
Stupor / 
coma
*Nitroprusside reaction method
**calculation: 2[measured NA (mEq/L)] + glucose (mmol/L)
***calculation:  (Na+) – [Cl- + HCO3
-  (mEq/L)]
Severe hypoglycaemic episodes
Severe hypoglycaemic episodes are events requiring the assistance of another person to 
actively administer carbohydrate, glucagon or other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following the 


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return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
This includes fatal hypoglycaemic events.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.
Medical judgement should be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship
could be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative etiologies that could explain the event (e.g. preexisting or 
concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger.


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
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains
unchanged.
5.3.7
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
From signing the informed consent onwards through the Residual Effect Period (REP), until 
individual patient’s end of trial:

all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
the Investigator does not need to actively monitor the patient for AEs but should only
report relevant SAEs and relevant AESIs of which the Investigator may become aware of.
The REP is defined as 7 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.


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With receipt of any further information to these events, a follow-up SAE form has to be
provided. For follow-up information the same rules and timeline apply as for initial
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form.  The Investigator should determine the causal 
relationship to the trial medication and any possible interactions between the investigational 
drug(s).
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions.  

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases, pregnancy may occur in a clinical trial.  Once a subject has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
within 24 hours) a potential drug exposure during pregnancy (DEDP) to the Sponsor’s unique 
entry point (country-specific contact details will be provided in the ISF).  The Pregnancy 
Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the DEDP must be followed up and reported 
to the Sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical Trials 
(Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable.
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S)
Additional, optional, blood and urine samples will be collected at visits 4, 8, 11 and 15 for the 
analysis of exploratory biomarkers.  These samples will be stored for up to 15 years after the 


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end of the clinical trial and may be used for future exploratory analyses.  Samples will be 
shipped from the site to the central laboratory for short term storage.  These samples will be 
shipped in batches to BI or to a location where the analysis of biomarkers will be conducted 
or the samples will be stored.
5.5.1
Endpoints based on biomarkers
Not applicable.
5.5.2
Methods of sample collection
Blood and urine samples will be collected from patients who provide consent to the optional 
biomarker sample collection. A detailed description of sample collection, handling and 
shipment will be provided in the ISF / lab manual.     
5.5.3
Analytical determinations
After completion of the study, banked blood and urine samples may be used for further 
investigations, e.g., identification of novel biomarkers associated with cardio-metabolic or 
renal disease.  The different exploratory biomarkers will be analysed using fit-for-purpose 
validated assays at Boehringer Ingelheim or contracted laboratory vendor.
5.5.4
Biobanking
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
Measurements performed during this trial are standard or previously validated measurements 
and will be performed in order to monitor safety aspects and to determine PDs in an 
appropriate way.
The scheduled measurements are appropriate to see drug-induced changes in vital signs, 
standard laboratory values, ECG, biomarkers specific to efficacy of treatment of T1D and 
renal endpoints.  The primary and other endpoints are acceptable evaluations of safety and 
tolerability of an oral anti-diabetic drug.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should take place preferably between 7:00 AM and 11:00 AM (except Visits 4, 
8, 11 and 15). If a patient mistakenly takes the trial medication on the morning of a schedule 
visit before attending the clinic or comes in non-fasted where a fasting condition is required, 
the visit should be rescheduled for another day if possible and the patient should be reminded 
about the expected conditions when presenting at the clinic. The rescheduled visit must take 
place in a short enough time-frame so that the patient has sufficient trial medication available.
All patients are to adhere to the visit schedule as specified in the Flow Chart. If any visit has 
to be rescheduled, subsequent visits should follow the original visit date schedule. The trial 
medication packs contain sufficient medication to allow for these time windows.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
At each visit, assessments should be performed as indicated in the Flow Chart and as detailed 
in the respective protocol sections.
6.2.1
Screening and run-in period(s)
Screening Period

No trial procedures should be done unless the patient has consented to taking part in the 
trial.  Once consent has been obtained, the patient is considered to be enrolled in the trial 
and to have started screening.  The patient should be recorded on the enrolment log and 
be registered in the IRT system as a screened patient  

Screening procedures may be conducted over several days within the screening window.

If a patient is taking a RAAS inhibitor and may safely discontinue, in the opinion of the 
investigator, patients may commence a wash-out of their prescribed RAAS inhibitor after 
signing the informed consent form for study participation.  Screening lab results may also 
be reviewed prior to commencing RAAS wash-out, at the discretion of the investigator.
Patients must not take the prescribed RAAS inhibitor for a minimum of 2 weeks prior to 
commencing with visit 2 activities.  During the wash-out period, if the patient need to re-
start their prescribed RAAS inhibitor therapy, the patient must be screen failed.

A lab test may be repeated during the screening period if the lab results were not provided 
by the central lab (e.g. the lab test was deleted) or if the lab results are inconsistent with 
the patient’s medical history.

BP should always be taken before any blood samples are taken.  Refer to Section 5.2.4.

A glucose / ketone meter with all the necessary supplies for home monitoring of glucose 
and ketones will be given to patients with T1D or patients who use insulin to manage 
their diabetes.  T2D patients who manage their diabetes with anti-hyperglycaemic agents, 
other than insulin, will be provided with a glucometer and required supplies.  Ketone 
strips may be provided if ketone monitoring is deemed necessary by the investigator.  Site 
staff must provide instruction on how to use the meter.  Patients will be provided with a 
diary to record values (to be completed daily).


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
Dietary requirements for the trial should be discussed at Visit 1.  Patients will be 
instructed to follow a healthy diet and exercise program during the course of the study 
except from the 7 days prior to renal assessments.  Patients should understand that they 
will need to follow the modified (sodium rich, moderate protein) diet for 1 week 
preceding the renal assessments.  

Visit 2 can be conducted as a phone visit. Site staff should remind the patient to start the 
modified diet. 

24 hour urine collection and ABPM must be performed after the patient has been 
following the modified diet but prior to the renal assessments.  It is recommended that the 
patient return to the clinic on the following day to return the urine collection container 
and to remove the ABPM device.  If the patient is not able to return to the clinic, the site 
staff must instruct the patient on how to remove the ABPM device and how to properly 
store the urine collection container.

One day prior to the renal assessments, the patient must take a 300 mg lithium tablet with 
a small amount of water.  Site staff should provide the lithium tablet to the patient when 
the patient is in the clinic to have the ABPM device attached.

Renal assessments will be performed one day prior to start of open label ramipril 
treatment.  Patients should report to the renal physiology lab by 7:30 am.  

After all renal assessments have been completed at visit 4, run-in medication must not be 
dispensed until after the GFR results are available (i.e. at visit 4a).  The patient may be 
included in the run-in if the patient’s GFR from visit 4 is ≥135 ml/min/1.73m2 or if 
enrolment of normofilterer patients is still permitted (refer to section 3.3). 
Run-in Period

At visit 4a, the site staff should contact the IRT to obtain a ramipril kit number. Ramipril 
administration should occur while the patient is in the clinic by the investigator or 
delegated site staff.  

Patients will receive a home BP monitor so that they may monitor their BP while taking 
the study medications.  Site staff must provide instruction on how to use the device.  BP 
readings may be recorded in the patient diary.

After the start of ramipril treatment and following dose titration to 10 mg ramipril, site 
staff should contact the patient daily for approximately 5 days to ensure that the patient is 
tolerating the dose adjustment. 

An unscheduled visit may be performed if the patient is experiencing side effects to the 
ramipril treatment. At the discretion of the Investigator, a lower dose of ramipril may be 
ordered through the IRT.  

One day prior to the renal assessments, the patient must take a 300 mg lithium tablet with 
a small amount of water.  Site staff should provide the lithium tablet to the patient when 
the patient is in the clinic to have the ABPM device attached.

At visit 8 after all renal assessments have been completed, the patient’s eligibility should 
be confirmed and eligible patients should be randomised to treatment through the IRT.  
The site staff should dispense the study medication and instruct the patient not to take the 
study medication (ramipril and empagliflozin /placebo) until the following morning (i.e. 
Day 1).  The patient should be instructed to record the actual date and time of medication 
in-take in their patient diary.


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
During the recruitment phase of the study, close monitoring of baseline GFR (at visit 8) 
will be done to ensure that clinically, a sufficient number of patients with renal 
hyperfiltration are included in the study.
6.2.2
Treatment period(s)
6.2.2.1
Period 1 dosing

It is recommended that the patient should not initiate double-blind treatment with 
empagliflozin/placebo if the patient is unwell (i.e., experiencing an acute illness like a flu 
or cold).  Treatment should be delayed until the patient has recovered from the acute 
illness.

If the patient was unable to tolerate the 10 mg ramipril dose during run-in, the patient 
may continue on the lower dose throughout the treatment period including the wash-out 
period.

Starting Day 1 and for approximately the next 5 days, patients must be followed up daily 
(phone calls) to ensure that all study safety and efficacy procedures are adequately 
followed.  

Visit 9 may be completed as a phone visit.  Patients should be instructed to start their 
modified diet one week prior to the renal assessments.

The 24 hour urine collection and ABPM should be performed once the patient is on the 
modified diet and at least 24 hours prior to the start of the renal assessments.

One day prior to the renal assessments, the patient must take a 300 mg lithium tablet with 
a small amount of water.  Site staff should provide the lithium tablet to the patient when 
the patient is in the clinic to have the ABPM device attached.

At visit 11, all study medications should be returned to the clinic.  The IRT system will 
assign a new ramipril kit to be taken during the wash-out period.
6.2.2.2
Wash-out

Starting Day 29 and for approximately the next 5 days, patients must be followed up daily 
(phone calls) to ensure that all study safety and efficacy procedures are adequately 
followed.

If the patient’s ramipril dose was down titrated during Period 1 dosing, the patient’s 
ramipril dose should be up-titrated during the wash-out period to their maximum tolerated 
dose which ideally is the same dose of ramipril that they started Period 1 dosing with.

Visit 12 will be at the end of the wash-out period.  At this visit, ramipril from the ramipril 
kit dispensed at the previous visit should be administered to the patient prior to collecting 
the kit.

A new ramipril kit and empagliflozin/placebo kit will be assigned via IRT. The site staff 
should dispense the study medication and instruct the patient not to take the study 
medication (ramipril and empagliflozin /placebo) until the following morning (i.e. Day 
57).  The patient should be instructed to record the actual date and time of medication in-
take in their patient diary.


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6.2.2.3
Period 2 dosing

It is recommended that the patient should not initiate double-blind treatment with 
empagliflozin/placebo if the patient is unwell (i.e., experiencing an acute illness like a flu 
or cold).  Treatment should be delayed until the patient has recovered from the acute 
illness.

The patient should start Period 2 with the same ramipril dose that they were on at the start 
of Period 1 dosing or their maximum tolerated dose during wash-out (refer to Section
4.1.3).

Starting on Day 57 and for approximately 5 days, patients must be followed up daily 
(phone calls) to ensure that all study safety and efficacy procedures are adequately 
followed.  

Visit 13 may be completed as a phone visit.  Patients should be instructed to start their 
modified diet one week prior to the renal assessments.

The 24 hour urine collection and ABPM should be performed once the patient is on the 
modified diet and at least 24 hours prior to the start of the renal assessments.

One day prior to the renal assessments, the patient must take a 300 mg lithium tablet with 
a small amount of water.  Site staff should provide the lithium tablet to the patient when 
the patient is in the clinic to have the ABPM device attached.
6.2.2.4
Unscheduled visits during the treatment period

At any point in time during the study, an unscheduled visit may occur to ensure patient 
safety.

If the patient is experiencing hypotension or other side effects known to occur with 
ramipril treatment, the patient may come for an unscheduled visit and have a dose 
adjustment.  7.5 mg or 5 mg b.i.d. should be tried initially so that the total daily dose
remains unchanged.  If side effects persist with a 10 mg total daily dose, the patient may 
be further down titrated.  All medication kits should be ordered through the IRT.

Select study procedures may be performed at these visits per Investigator judgement.  
These procedures may include, but are not limited to, additional safety laboratory tests, 
vital signs, physical examination, diabetes diet and exercise counselling or insulin dose 
adjustment.
6.2.3
Follow Up Period and Trial Completion

The final treatment visit is visit 15.  All study medications must be returned at visit 15.  
All patients should return to the clinic for their final follow-up visit (visit 16).

Although patients have stopped taking the study medications, the patients should be 
contacted by phone for approximately 5 days, to ensure that all study safety procedures 
are adequately followed.  
6.2.3.1
Early end of treatment visit (eEOT)

The eEOT visit is only required for those patients who discontinue from the trial early.

If a patient discontinues from the trial early (after the start of ramipril study medication), 
an eEOT visit should be done as soon as feasible. 


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
These patients should return to the clinic for an additional follow up visit (Visit 16). If 
feasible, early discontinued patients should continue with SBGM until Visit 16.

All AEs should be collected until the end of the REP (i.e., 7 days after the last medication 
intake) for patient who discontinue from treatment early.  Refer to Section 5.3.7.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This is a randomised, double-blinded, placebo-controlled 2x2x2 (2-treatment, 2-sequence, 2-
period) crossover, single-centre trial.
The primary objective is to assess the effect of the addition of empagliflozin to ramipril on 
reducing GFR in patients with T1D, T2D or obesity who have GFR ≥ 135 mL/min/1.73 m2
(under euglycaemic conditions) after ramipril monotherapy. 
Patients who successfully complete the open-label ramipril run-in period and meet the
inclusion/exclusion criteria will be randomised into the trial, with no stratification, to one of 
two sequences; empagliflozin-placebo (A) or placebo-empagliflozin (B). 
Efficacy analysis of this trial will be based around four subgroups of patients defined by 
baseline GFR measurements under euglycaemic conditions:

Hyperfilterers: Patients before ramipril monotherapy with GFR ≥ 135 mL/min/1.73 m2, as 
measured at screening (visit 4)

Non-responders: Patients after ramipril monotherapy with GFR ≥ 135 mL/min/1.73 m2, 
as measured at randomisation (visit 8)

Responders: Patients after ramipril monotherapy with GFR < 135 mL/min/1.73 m2, as 
measured at randomisation (visit 8)

Normofilterers: Patients before ramipril monotherapy with GFR < 135 mL/min/1.73 m2, 
as measured at screening (visit 4)
Note Non-responders and Responders are a subset of the Hyperfilterers.
These subgroup definitions will be used throughout. The primary efficacy analysis of this 
trial will be based around the hyperfilterers subgroup. Secondary and further efficacy analysis 
will focus on the other subgroups and overall. Safety analysis will primarily focus upon all 
treated patients, but secondary analysis by GFR subgroup will also be performed.
Restricted Maximum Likelihood Estimation (REML) based Mixed-effects Model for 
Repeated Measures (MMRM) analysis will be used to obtain adjusted means for the 
treatment effects. This model will include treatment and period as fixed effects, patient as a 
random effect and randomisation baseline (visit 8) as a covariate. Compound symmetry will 
be used as a covariance structure for within-patient variation.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Let µHA be the mean GFR under euglycaemic conditions after 4 weeks of treatment with 
ramipril and empagliflozin combination therapy in hyperfilterers.
Let µHB be the mean GFR under euglycaemic conditions after 4 weeks of treatment with 
ramipril and placebo combination therapy in hyperfilterers. 
Primary Objective Hypothesis:


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The primary objective of the trial will be addressed by a two-sided test at level α = 0.05. The 
following null and alternative hypotheses will be tested:
H0: µHA - µHB = 0
H1: µHA - µHB ≠ 0
The test of the null hypothesis will be supported by the 95 % confidence interval (CI) for µHA
- µHB and the null hypothesis will be rejected if the CI excludes 0 mL/min/1.73 m2.
7.3
PLANNED ANALYSES
Patients have been shown previously to respond differently to ramipril or empagliflozin 
depending upon their baseline GFR measurement [R10-6368], ATIRMA, [c01802271-02]. In 
particular, differential changes from baseline have been demonstrated above and below 135 
mL/min/1.73m2. The variance in the response without baseline adjustment has also been 
previously shown to vary with baseline GFR [c01802271-02].
Therefore, patients will be principally analysed by GFR subgroups, defined using GFR 
measurements at screening (visit 4) and randomisation (visit 8). Responder/non-responder 
subgroups will be defined using the randomisation measurement, which is on ramipril
treatment.  Normofilterer/hyperfilterer subgroups will be defined using the screening 
measurement, which is pre-ramipril treatment. The subgroup definitions are provided in 
Section 7.1. In general, efficacy analysis of this trial will be conducted by subgroup, although 
analysis will also be conducted across the full set.  If patient numbers are too low to allow a 
meaningful analysis for a subgroup then only a descriptive summary will be presented.
It should be noted that despite analysis being conducted by GFR status, no GFR-based 
stratification is performed at randomisation due to the length of time required for GFR results 
to be obtained. This is viewed to not be problematic as the crossover design ensures that 
balance is maintained between treatments within each subgroup. Randomisation will ensure 
that approximate balance is likely between sequences within subgroups and complete balance 
is not viewed as necessary as no sequence-related effects are foreseen.
The statistical analysis will be based on the following populations:
Run-In Set (RIS)
The run-in set (RIS) will consist of all patients who were treated with at least one dose of 
study drug (ramipril, empagliflozin and/or placebo).
Treated Set (TS)
The treated set (TS) will consist of all patients who were randomised and treated with at least 
one dose of empagliflozin/placebo.
Full Analysis Set (FAS)
The full analysis set (FAS) will consist of all patients who were randomised, treated with at 
least one dose of empagliflozin/placebo and provided randomisation baseline (visit 8) and at 
least one post-randomisation GFR measurement.
Per Protocol Set (PPS)


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There will be a per protocol set (PPS), the inclusion/exclusion criteria for which will be fully
defined in the TSAP.
Where subgroups of these sets are analysed, the subgroup will be described within the 
analysis description.
Patients will be analysed for efficacy according to the randomised treatment rather than the 
treatment actually received.
7.3.1
Primary endpoint analyses
7.3.1.1
Primary Analysis
The primary analysis of the primary endpoint will be performed upon the hyperfilterer 
subgroup of the FAS. Therefore, all randomised hyperfilterer patients (visit 4, GFR ≥ 135 
mL/min/1.73 m2 under euglycaemic conditions) who were treated with at least one dose of 
empagliflozin/placebo, had a randomisation (visit 8) baseline and at least one on-treatment GFR 
measurement will be included.
Comparisons between treatment groups for the primary endpoint will be based on a mixed 
effect repeated measures model (MMRM). This model will include treatment and period as 
fixed effects, patient as a random effect and (randomisation) baseline as a covariate. 
Compound symmetry will be used as a covariance structure for within-patient variation. The 
SAS procedure MIXED will be used involving the REML estimation method and the 
Kenward-Roger approximation for denominator degrees of freedom and standard error 
adjustment. This approach is described in Kenward and Roger [R10-4391]. Adjusted mean 
values as well as treatment contrasts will be presented together with the 95% CIs and p-
values.
The model is described by the following equation:
Yij = αi + j + ij + βSi + εij, where
Yij = GFR measured on patient i in period j,
αi = the random effect associated with the i’th patient, i = 1, 2, ..., n,
j = the j’th period effect, j = 1, 2,
ij = the effect of treatment applied to patient i in period j,
β = a fixed model coefficient,
Si = baseline GFR for patient i,
εij = the random error associated with the i’th patient in period j.
Baseline GFR will be defined as the GFR measurement obtained at randomisation (visit 8). 
The random errors εij are assumed to be independent, normally distributed with mean 0 and 
unknown variance σε². The random effects αi are assumed to be independent, normally 
distributed with mean 0 and unknown variance σα². εij are also assumed to be independent of 
αi.


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7.3.1.2
Secondary and sensitivity analyses

The following patient populations will be analysed using the same statistical methods as 
described for the primary analysis in Section 7.3.1.1:
-
Non-responders in the FAS
-
Responders in  the FAS
-
Normofilterers in the FAS
-
All patients in the FAS

An analysis of the primary endpoint on all patients in the FAS will be performed 
assuming that any treatment effect is linearly dependent upon randomisation baseline 
(visit 8) GFR. This will be performed using an adjusted MMRM model with an 
interaction term of treatment-by-baseline-GFR. The model will be fully specified in the 
TSAP.
The gradient of the treatment effect, with confidence interval will be estimated. Estimates 
for the treatment effect will also be provided for certain randomisation baseline GFR 
values. These will be within the range of randomisation baseline values observed, at 
intervals of 15 mL/min/1.73m2 and centred around the mean baseline value. 95% CIs will 
be provided for all estimates.

The previous analysis of the primary endpoint will be repeated on all patients in the FAS 
using the MMRM model with linear dependence of treatment effect upon baseline GFR 
using screening baseline (visit 4) GFR.

Treatment period 1 GFR response will be separately assessed by baseline-adjusted 
(randomisation, visit 8) ANCOVA for patients in the FAS for each of the following 
groups: 
-
all patients
-
hyperfilterers
-
non-responders
-
responders
-
normofilterers.

The natural logarithm of the primary endpoint will be analysed separately for 
hyperfilterers and all patients in the FAS. The MMRM model as described in Section 
7.3.1.1 will be used with the modification that all GFR measurements (including baseline)
will be replaced by their respective natural logarithms. Model outputs will be back-
transformed and the estimate of the treatment effect reported as the ratio of GFR after
empagliflozin and ramipril treatment divided by GFR on placebo and ramipril treatment, 
with 95% CI.

Sensitivity analyses of the primary endpoint will be performed as follows:
o
The primary analysis for the primary endpoint, as detailed in Section 7.3.1.1, will 
be repeated for the hyperfilterers from the PPS.


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o
The primary analysis for the primary endpoint, as detailed in Section 7.3.1.1, will 
be repeated on hyperfilterers in the FAS, excluding patients who were prescribed 
at any time with < 10 mg ramipril during the double blinded treatment periods. 
o
The primary endpoint analysis for the primary endpoint, as detailed in Section
7.3.1.1, will be repeated using a fixed effect for patient.
o
The primary endpoint analysis for the primary endpoint, as detailed in Section
7.3.1.1, will be repeated including sequence in the statistical model.
7.3.2
Secondary endpoint analyses
7.3.2.1
Primary Analysis
Filtration status, defined as whether GFR < 120 mL/min/1.73 m2, after 4 weeks of treatment 
with placebo added to ramipril or treatment with empagliflozin added to ramipril (yes/no).
This will be analysed for the population of hyperfilterers in the FAS. 
It will be statistically analysed by McNemar’s test [R15-3496], with the odds ratio, 95 % CI
and nominal p-value reported. It will also be descriptively analysed by the proportion with 
each status.
7.3.2.2
Secondary analyses
The following patient populations will be analysed using the same statistical methods as 
described for the primary analysis in Section 7.3.2.1:
-
All patients in the FAS
-
Non-responders in the FAS
In addition further analyses using different threshold values may be performed, to be defined 
in the TSAP.


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7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 
coding dictionary. Standard BI summary tables and listings will be produced. All AEs with 
an onset between start of treatment and end of the REP, a period of 7 days after the last dose 
of trial medication, will be assigned to the treatment period for evaluation.
All treated patients will be included in the safety analysis and reporting will be by actual 
treatment at onset. In general, safety analyses will be descriptive in nature and will be based 
on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the REP will be considered 
‘treatment-emergent’.  The REP is defined as 7 days after the last dose of 
empagliflozin/placebo. AEs that start before first drug intake and deteriorate under treatment 
will also be considered as ‘treatment-emergent’.
AEs occurring prior to first intake of any trial medication will be assigned to ‘screening’. AEs 
occurring from first pre-randomisation intake of ramipril until first intake of 
empagliflozin/placebo will be assigned to ‘run-in’. AEs occurring while on 
empagliflozin/placebo or up to 7 days after intake will be assigned to the relevant double-
blind treatment period. AEs occurring during the washout period and more than 7 days after 
intake of empagliflozin/placebo will be assigned to ‘washout’. AEs occurring more than 7 
days after final intake of empagliflozin/placebo in the second period will be assigned to ‘post-
study’. More details of the assignments, including the corresponding time intervals will be 
defined in detail in the TSAP.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


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7.4
INTERIM ANALYSES
Although a DMC will review the safety data on an ongoing basis (see Section 3.1.1.4), no 
formal interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Patients missing all post-randomisation GFR data are omitted from the FAS, as are those 
missing either or both the screening baseline (visit 4) and randomisation baseline (visit 8) 
GFR measurement. 
For analyses by MMRM, missing response data will not be imputed: MMRM is a likelihood 
based method and as such can implicitly account for data that is Missing At Random (MAR).
For analyses by McNemar’s test, a missing binary response will not be imputed and will 
implicitly be treated by the analytical method as being the same as the patient’s evaluable 
response for the other period. 
For the ANCOVA analysis of period 1 only, patients missing a period 1 measurement will be 
excluded from the analysis. For the analysis of pre-randomisation GFR, patients missing 
either GFR measurement will be excluded. For all other further endpoints, patients missing 
both post-randomisation continuous measurements will be implicitly excluded by the 
MMRM method, while patients missing one or both binary measurements will also be 
omitted from analysis (implicitly treating the two measurements as being the same).
Methods to handle any other exceptional cases will be considered before unblinding the data 
and will be applied in a manner consistent with other trials of this type. The evaluability of 
patients with deviations from the protocol likely to confound the treatment response will be 
decided prior to unblinding.
7.6
RANDOMISATION
After measurement of baseline characteristics there will be an open-label run-in period of 4
weeks. The trial will then be performed as a double-blind design with respect to the two 
treatment sequences in the subsequent periods (ramipril+empagliflozin then ramipril+placebo 
and ramipril+placebo then ramipril+empagliflozin). Ramipril medication will be unblinded 
throughout as it does not vary between treatments.
At the end of the run-in period, patients will be randomised in blocks to the two study 
sequences in a 1:1 ratio. There will be no stratification at randomisation by GFR for logistical 
reasons.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the CTR. Access to the codes will be 
controlled and documented.


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7.7
DETERMINATION OF SAMPLE SIZE
In a previous study [R10-6368], it was found that the change in GFR from baseline after 8 
weeks of treatment with ramipril in hyperfilterers was -34.9 mL/min/1.73m2 (no CI specified, 
unadjusted for baseline). The mean baseline GFR for this sample was 177.7 mL/min/1.73m2. 
In a separate study (ATIRMA, [c01802271-02]), it was found that the change in GFR from 
baseline after 8 weeks of treatment with empagliflozin monotherapy in hyperfilterers was -
33.4 mL/min/1.73m2 (95% CI: -46.2 to -20.6 mL/min/1.73m2); this was also unadjusted for 
baseline and the mean baseline GFR for this sample was 172.2 mL/min/1.73 m2. It is believed 
that response after 8 weeks treatment will be similar to response at 4 weeks.
The combination of ramipril and empagliflozin has not been investigated in clinical trials 
before so the extent of the additivity of their GFR reduction effects is unknown. Baseline 
GFR while on ramipril treatment (randomisation baseline) is likely to be considerably lower 
than before treatment (screening baseline): 
From the ATIRMA trial, the effect of empagliflozin was found to be correlated with baseline 
GFR (r = -0.78, r2 = 0.60). From all of this, it is therefore believed that an additional change 
in GFR from baseline of approximately -15 mL/min/1.73m2 in hyperfilterers is likely for the
combination treatment in comparison to the monotherapy.
In the same trial, the standard deviation of the change from baseline between individuals was 
found to be 35.3 mL/min/1.73m2. However, this accounted for neither the strong negative 
correlation with baseline GFR, nor any correlations with other baseline characteristics that 
are inherently adjusted for in a cross-over trial by the use of within-subject comparisons. 
For this crossover design, it is estimated that there is strong correlation between a subject’s 
measurements of between ρ = 0.68 and 0.75. This is a reasonable range since r2 between 
baseline and change from baseline was previously found to be 0.60, which does not account 
for any other baseline covariates. Total standard deviation () may be related to within-
subject standard deviation () by the following formula:
 = (1 −)
Consequently, it is estimated that the intra-individual standard deviation is likely to be in the 
range of 17.5 to 20 ml/min/1.73m2.
Under the assumptions of an effect size of -15 mL/min/1.73m2, an intra-individual standard 
deviation of 17.5 mL/min/1.73m2, a two-sided type I error rate of 0.05, and power of 90%, it 
was calculated that 16 hyperfilterer patients would be required per arm (i.e. treatment 
sequence) to demonstrate superiority, giving a total of 32 hyperfilterers. Including an 
additional 2 hyperfilterers to account for dropout, the minimum required sample size is 34
hyperfilterers. 
As there is some uncertainty over the likely intra-individual standard deviation, Table 7.7:1
provides the power for a range of assumed standard deviations and effect sizes. From this, it 
can be seen that the trial is also reasonably-powered (82.7%) to detect the same effect size of 
-15 ml/min/1.73m2 if the intra-individual standard deviation is 20.0 ml/min/1.73m2, and has 
approximately 76% power to detect a smaller effect size of -12 ml/min/1.73m2 if the intra-
individual standard deviation is 17.5 mL/min/1.73m2.


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Table 7.7: 1
Power for a 2x2 crossover design with 16 hyperfilterers per arm under 
varying assumptions of effect size and intra-individual standard 
deviations. Calculations were performed using nQuery Advisor® 7.0
statistical package by Statistical Solutions Ltd.
Intra-Individual Standard Deviation, 
ml/min/1.73m2 (corresponding ρ)
Effect Size 
mL/min/1.73m2
15.8 
(0.80)
17.5 
(0.75)
20.0 
(0.68)
22.3 
(0.60)
-10
68.7%
59.9%
49.0%
41.1%
-12
83.6%
75.6%
64.1%
54.9%
-15
95.6%
91.2%
82.7%
74.0%
-18
>99.0%
97.8%
93.6%
87.7%
In summary, the sample size will be based upon the number of hyperfilterers, and will be a 
minimum of 34 hyperfilterers. The number of patients required to be randomised to provide 
this is expected to be approximately 74.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for GCP, relevant BI Standard Operating Procedures (SOPs), and relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP*.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / IEC and competent authority (CA) according to national 
and international regulations. The same applies for the implementation of changes introduced 
by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
(e)CRF for individual patients will be provided by the Sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.


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8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
Data should be transcribed into the eCRF based on the information contained within the 
source documents. 
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRF/eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The CRA / on site monitor 
and auditor may review all CRF / eCRF, and written informed consents. The accuracy of the 
data will be verified by reviewing the documents described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular AE is "listed", i.e. is a known side effect of the drug or not. Therefore, a 
unique reference document for the evaluation of listedness needs to be provided. For 
empagliflozin this is the current version of the IB (applicable Doc. No: c01678844-07). For 
the ramipril this is the Canadian Product Monograph. The current versions of these reference 
documents are to be provided in the ISF.
8.4.2
Expedited reporting of adverse events 
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.


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8.6 
END OF TRIAL
The end of the trial is defined as in Section 6.2.3.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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FC.  Kidney in diabetes: from organ damage target to therapeutic target.
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P13-16965
Cherney DZI, et al. Renal hemodynamic effect of sodium-glucose 
cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 
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P16-01830
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, 
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Shift to fatty substrate utilization in response to sodium.glucose cotransporter 
2 inhibition in subjects without diabetes and patients with type 2 diabetes. 
Diabetes 65 (5), 1190 - 1195 (2016)
P16-06807
Wanner C, Inzucchi SE, Lachin JM, Fitchett D. Eynatten M von, et al., 
EMPA-REG Outcome Investigators. Empagliflozin and progression of kidney 
disease in type 2 diabetes.  N. Engl J Med 2016; 375(4), 323-334.
R96-3187
ZatzR, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. 
Prevention of diabetic glomerulopathy by pharmacological amelioration of 
glomerular capillary hypertension. J Clin Invest 1986; 77 (6), 1925 – 1930
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Lewis EJ, Hunsicker LG, Bain RP, Rohde RD.  The effect of angiotensin-
converting-enzyme inhibition on diabetic nephropathy. The Collaborative 
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Brenner BM, et al, RENAAL Study Investigators. Effects of losartan on renal 
and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. 
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R04-2173
Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, Frighi V, 
Manley SE, Neil A, McElroy H, Wright D, Kohner E, Fox C, Hadden D, UK 
Prospective Diabetes Study Group. Intensive blood-glucose control with 
sulfonylureas or insulin compared with conventional treatment and risk of 
complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352, 
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The Diabetes Control and Complications Trial Research Group
The effect of intensive treatment of diabetes on the development and 
progression of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med 1993; 329 (14), 977 - 986 
R05-0939
Wright EM, Turk E. The sodium/glucose cotransport family SLC5.
Pfluegers Arch 2004; 447 (5), 510 – 518


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R09-2151
Guidance for industry:  diabetes mellitus – evaluating cardiovascular risk in 
new antidiabetic therapies to treat type 2 diabetes (Dec 2008).  Silver Spring:  
US Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2008.
R10-0703
Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. 
Glucose transporters in human renal proximal tubular cells isolated from the 
urine of patients with non-insulin-dependent diabetes. Diabetes 2005: 54 (12), 
3427 – 3434
R10-4391
Kenward MG, Roger JH.  The use of baseline covariates in crossover studies.
Biostatistics 2010; 11 (1), 1 – 17
R10-6364
Cherney DZI, et al. Renal hemodynamic effect of cyclooxygenase 2 inhibition 
in young men and women with uncomplicated type 1 diabetes mellitus. Am J 
Physiol 2008: 294, F1336 - F1341
R10-6368
Sochett EB, Cherney DZI, Curtis JR, Dekker MG, Scholey JW, Miller JA. 
Impact of renin angiotensin system modulation on the hyperfiltration state in 
type 1 diabetes.J Am Soc Nephrol 2006; 17, 1703 – 1709
R10-6369
Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tabini CC, Montori VM
Hypoglycemia with intensive insulin therapy: a systematic review and meta-
analyses of randomized trials of continuous subcutaneous insulin infusion 
versus multiple daily injections.  J Clin Endocrinol Metab 2009; 94 (3), 729 –
740
R10-6374
Cherney DZI, et al.  Renal hyperfiltration is a determinant of endothelial 
function responses to cyclooxygenase 2 inhibition in type 1 diabetes. Diabetes 
Care 2010: 33 (6), 1344 - 1346
R10-6380
Mustata S, Chan C, Lai V, Miller JA.  Impact of an exercise program on 
arterial stiffness and insulin resistance in hemodialysis patients. J Am Soc 
Nephrol 2004: 15 (10), 2713 - 2718
R10-6572
Mogensen CE.  Maximum tubular reabsorption capacity for glucose and renal 
hemodynamics during rapid hypertonic glucose infusion in normal and 
diabetic subjects. Scand J Clin Lab Invest 1971: 28 (1), 101 – 109
R11-0072
Cherney DZI, et al.  Age is a determinant of acute hemodynamic responses to 
hyperglycemia and angiotensin II in humans with uncomplicated type 1 
diabetes mellitus. Am J Physiol 2010:299 (1), R206 - R214
R12-1489
Diabetes Control and Complications Trial/Epidemiology of Diabetes 
Interventions and Complications (DCCT/EDIC) Study Research Group
Intensive diabetes treatment and cardiovascular disease in patients with type 1 
diabetes. N Engl J Med 2005; 353 (25), 2643 - 2653 


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R12-5147
Vallon V, Richter K, Blantz RC, Thomson S, Osswald H.  Glomerular 
hyperfiltration in experimental diabetes mellitus: potential role of tubular 
reabsorption. J Am Soc Nephrol 1999; 10, 2569 - 2576 
R14-0982
Seaquist ER, et al.  Hypoglycemia and diabetes: a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diabetes Care 
2013; 36 (5), 1384 - 1395 
R14-5435
American Diabetes Association.  Standards of Medical Care in Diabetes –
2014. Diabetes Care 37 (Suppl. 1), pp S14-S80
R15-3480
Koomans HA, Boer WH, Mees EJD.  Evaluation of lithium clearance as a 
marker of proximal tubule sodium handling. Kidney Int 1989; 36 (1), 2 – 12
R15-3481
Montanari A, et al.  Renal hemodynamic response to L-arginine in 
uncomplicated, type 1 diabetes mellitus: the role of buffering anions and 
tubuloglomerular feedback. Am J Physiol 2012; 303, F648 - F658
R15-3482
Marik, PE. Noninvasive cardiac output monitors: a state-of-the-art review.  J 
Cardiothoracic and Vasc Anesthesia 2013; 27(1), 121-134
R15-3496
McNemar Q. Note on the sampling error of the difference between correlated 
proportions or percentages. Psychometrika 1947; 12 (2), 153 – 157.
R18-1327
Chagnac A, Herman M, Zingerman B, Erman A, Rozen-Zvi B, Hirsh J, et al. 
Obesity-induced glomerular hyperfiltration:  its involvement in the 
pathogenesis of tubular sodium reabsorption.  Nephrol. Dial. Transplant 2008; 
23(12), 3946-3952.
R18-1328
Cogan, MC.  Angiotensin II:  a powerful controller of sodium transport in the 
early proximal tubule.  Hypertension  1990; 15(5), 451-458.
R18-1329
Zoccali C.  Overweight, obesity and metabolic alterations in chronic kidney 
disease. Prilozi 2009; 30(2), 17-31.
R18-1330
Praga M, Morales E. The fatty kidney:  obesity and renal disease. Nephron 
2017; 136(4), 273-276.
R18-1807
Delanaye P, Ebert N, Melsom T, Gaspari F, Mariat C, Cavalier E, Bjork J, 
Christensson A, Nyman U, Porrini E, Remuzzi G, Puggenenti P, Schaeffner E,
Soveri I, Sterner G, Erikson BO, Back, SE.  Iohexol plasma clearance for 
measuring glomuerular filtration rate in clinical practice and research:  a 
review.  Part 1:   How to measure glomerular filtration rate with iohexol?  Clin 
Kidney J. 2016; 9(5), 682 – 699.


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R18-1808
Delanaye P, Melsom T, Ebert N, Back SE, Mariat C, Cavalier E, Bjork J, 
Christensson A, Nyman U, Porrini E, Remuzzi G, Ruggenenti P, Schaeffner E, 
Soveri I, Sterner G, Eriksen BO, Gaspari F.  Iohexol plasma clearance for 
measuring glomuerular filtration rate in clinical practice and research:  a 
review.  Part 2:  Why to measure glomerular filtration rate with iohexol?  Clin 
Kidney J. 2016; 9(5), 700-704.
9.2
UNPUBLISHED REFERENCES
c01678844-07 Investigator Brochure, Empagliflozin (BI 10773)
c01802271-02
An open-label 8-week 
adjunctive-to-insulin and renal mechanistic pilot trial of BI 10773 in type 1 
diabetes mellitus (the ATIRMA trial). 1245.46 Clinical Trial Report, 28-
Mar-14 
c02435449-01
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-1). 1245.78 Clinical Trial 
Report, 05-Feb-15
c11963611-01
  An open-label, mechanistic 
study to examine the effect of oral empagliflozin (25 mg q.d.) on kinetics of 
renal glucose reabsorption in patients with type 2 diabetes mellitus and 
healthy controls.  1245.66 Clinical Trial Report, 28 Mar 2017
U12-2707-01
SCS appendix and integrated summary of safety 08 Feb 2013


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1.0
Date of CTP revision
26 Apr2016
EudraCT number
NA
BI Trial number
1245.100
BI Investigational Product(s)
Empagliflozin
Title of protocol
A double-blind, placebo controlled, cross-over 
renal mechanistic trial to assess the effect of adding 
empagliflozin versus placebo on renal 
hyperfiltration in patients with type 1 diabetes on a 
background of the angiotensin converting enzyme 
inhibitor (ACEi) ramipril:  BETWEEN Study
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
X
Section to be changed
Flow Chart
Description of change
“X” removed for the collection of biomarker 
samples being collected at the follow-up visit. 
Rationale for change
To make the flow chart consistent with section 5.5.
Section to be changed
Flow Chart
Description of change
“X” added to ECG at the follow-up visit. 
Rationale for change
To make the flow chart consistent with section 
5.3.4.
Section to be changed
Foot notes to the flow chart
Description of change
Foot note 2 was revised to indicate that 3 sets of 
BP measurements would be collected at routine 
clinic visits. “Postural vitals” was removed.
Rationale for change
To make the flow chart foot notes consistent with 
section 5.2.4.1 and 5.2.4.2.


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Section to be changed
Foot notes to flow chart
Description of change
Foot note 14 was updated to reflect administration 
of study medication in the morning and that the 
arterial stiffness, NICOM, SNS measurements and 
lab samples (renal panel) will be collected prior to 
sample collect for inulin and PAH.  Per table 
5.3.3:1 footnote 1, BHB sample collecting times 
were included.
Rationale for change
To make the foot note instructions consistent with 
other sections of the protocol (section 4.1.4, 5.3.3).
Section to be changed
3.1
Description of change
Assessment day -29 was changed to -28
Rationale for change
To make the day for the renal assessments 
consistent with the flow chart.
Section to be changed
4.1.1
Description of change
Added Valeant Pharmaceuticals as another source 
of ramipril.
Rationale for change
Ramipril re-supply medication was purchased from 
 as 
 was no 
longer supplying ramipril in 
Section to be changed
4.1.4
Description of change
Correct the study day that Ramipril is started.
Rationale for change
To make this section consistent with the flow chart.
Section to be changed
4.2.1
Description of change
Guidance is provided for insulin reductions when 
starting blinded study medication.  It was clarified 
that daily ketone monitoring should occur prior to 
breakfast.
Rationale for change
Clarification / optimisation of suggested insulin 
titration and alignment with phase III trials.
Section to be changed
4.2.2.2
Description of change
Correct the day when the modified diet should be 
started and to correct the last study visit number.
Rationale for change
To make this section consistent with the flow chart.
Section to be changed
Description of change


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Rationale for change
Section to be changed
5.2.4.2
Description of change
Reference to postural blood pressure was removed.
Rationale for change
Postural vitals could be mis-interpreted as 
‘orthostatic’ blood pressure which is not required 
for this trial.  Routine BP measurements will be 
taken consistently throughout the study following 
the procedure outlined in section 5.2.4.1.
Section to be changed
5.3.5.2
Description of change
It was clarified that all hypoglycaemias will not be 
reported in the eCRF but they will be documented.
Rationale for change
To ensure consistency with reporting in other trials.
Section to be changed
5.3.6.1
Description of change
The section for “always serious AEs” was updated 
to describe the list of AEs as a list of further AEs.
Rationale for change
To make the section consistent with the current 
version of the CTP template.
Section to be changed
7.3
Description of change
Names of analysis sets were revised.
Rationale for change
To make the names of the analysis sets consistent 
with project standards.
Section to be changed
7.3.1.1
Description of change
Modification of the description of the REML and 
Kenward Roger methods being used.
Rationale for change
To clarify the effect of the methods specified.
Section to be changed
7.3.1.2
Description of change
Modification of pre-specified output from 
secondary analyses based upon the treatment-by-
baseline interaction model. Change of criteria for 
sensitivity analysis excluding <10 mg ramipril dose 
patients from treated to prescribed.


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Rationale for change
Outputs as specified were insufficiently different 
from estimates of treatment effect at given baseline 
values already being calculated. Criteria for dose 
assignment aligned with other analyses.
Section to be changed
Description of change
Rationale for change
Section to be changed
8.4.1
Description of change
The document used for listedness for Ramipril was 
changed from the SmPC to the Canadian Product 
Monograph.
Rationale for change
Since this was a single centre study that is being 
conducted in Canada, the Canadian label would be 
used for assessing listedness.
Section to be changed
8.4.2
Description of change
BI is the responsible party for expedited reporting 
of AEs.
Rationale for change
To clarify the reporting responsibilities.


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Number of global amendment
2.0
Date of CTP revision
22 Sep 2016
EudraCT number
NA
BI Trial number
1245.100
BI Investigational Product(s)
Empagliflozin
Title of protocol
A double-blind, placebo controlled, cross-over 
renal mechanistic trial to assess the effect of adding 
empagliflozin versus placebo on renal 
hyperfiltration in patients with type 1 diabetes on a 
background of the angiotensin converting enzyme 
inhibitor (ACEi) ramipril:  BETWEEN Study
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synposis – Main criteria for inclusion
Description of change
Changed HbA1c lower limit from 7% to 6.5%.
Rationale for change
To reduce the number of patients, who are 
otherwise suitable, but screen fail due to an HbA1c
value that is just below 7%.
Section to be changed
2.3 Benefit – Risk Assessment
Description of change
Investigators should differentiate deteriorating 
ketosis / DKA from any milder ketone values.  
Rationale for change
To provide guidance on safety monitoring.
Section to be changed
3.3 Description of Trial Population
Description of change
Instructions on re-screening patients has been 
included.
Rationale for change
To permit re-screening of patients who have screen 
failed but could be re-screened if the patient was 
considered to be a good potential candidate for the 
trial.
Section to be changed
3.3.2  Inclusion criteria #4


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Description of change
HbA1c value was changed from 7% to 6.5%
Rationale for change
To reduce the number of patients, who are 
otherwise suitable, but screen fail due to an HbA1c
value that is just below 7%.
Section to be changed
3.3.2 Inclusion criteria # 10
Description of change
Removed tubal occlusion as a method of surgical 
sterilization per ICH M3 (R2) guidance.
Rationale for change
Tubal ligation is considered to be a highly effective 
method of contraception and no longer a method of 
permanent sterilisation
Section to be changed
3.3.3 Exclusion criteria #4
Description of change
Severe hypoglycaemia involving unconsciousness 
was added.
Rationale for change
Adjustment of eligibility for safety reasons and for 
clarification.
Section to be changed
4.2.2.2  Restrictions on diet and lifestyle
Description of change
Extreme diets such as the ketogenic diet are 
prohibited during the trial.
Rationale for change
Add for clarification of patient safety.
Section to be changed
5.2.1 Haemodynamic measurements
Description of change
Included measurement of haematocrit every 30 min 
once equilibrium has been achieved.
Rationale for change
Omitted in error from previous version of protocol
Section to be changed
5.2.2 Segmental tubular handling of sodium
Description of change
Blood and urine samples will be collected at 3 
time-points.  Types of samples collected are 
included.
Rationale for change
Clarification of sample collection.
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
Removed statement that re-screening is not 
permitted.
Rationale for change
Re-screening will be permitted in the study.
Section to be changed
Various sections
Description of change
IB reference number has been changed from 
c01838761 to c01678844-07
Rationale for change
Updated IB version was assigned a different 
document number.


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Number of global amendment
3.0
Date of CTP revision
03 Jul 2018
EudraCT number
NA
BI Trial number
1245.100
BI Investigational Product(s)
Empagliflozin
Title of protocol
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
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title Page
Description of change
Reference to type 1 diabetes patients was removed 
from the protocol title.
Rationale for change
The trial is proposed to recruit patients who have 
type 1 diabetes, type 2 diabetes or are obese.  
Therefore a strict reference to type 1 patients was 
removed to reflect revision to the protocol entry 
criteria.
Section to be changed
Clinical Trial Protocol  Synopsis
Description of change
Reference to type 1 diabetes patients was removed 
from the protocol title and objectives.
Rationale for change
The trial is proposed to recruit patients who have 
type 1 diabetes, type 2 diabetes or are obese.  
Therefore a strict reference to type 1 patients was 
removed to reflect revision to the protocol entry 
criteria.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Planned number of patients changed from 62 to 74 


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with 37 patients in each treatment group.
Rationale for change
Number of patients adjusted according to sample 
size re-calculation.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Type 2 diabetes and obesity is added to the 
diagnosis and main inclusion criteria. 
Abbreviations for type 1 diabetes and type 2 
diabetes were added.
Rationale for change
The trial is proposed to recruit patients who have 
type 1 diabetes, type 2 diabetes or are obese.  
Therefore diagnosis and main inclusion criteria is 
updated accordingly.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Duration for screening period lengthened from 2 
weeks to 4 weeks.
Rationale for change
To permit possible wash-out of RAAS inhibitors 
which may be safely discontinued.
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Updated definition of filtration status is defined as 
GFR < 120 ml/min/1.73m2.
Rationale for change
The primary efficacy subgroup of patients has 
changed from non-responders to hyperfilterers, 
GFR filtration status threshold value lowered as 
lower baseline GFR values expected in this 
subgroup. 
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
The primary analysis will be conducted in patients 
who have a GFR ≥ 135 ml/min/1.73m2 at visit 4 
rather than at visit 8.
Rationale for change
ACE-I non-responder analysis will be a sub-group 
analysis rather than the primary analysis.
Section to be changed
Flow Chart
Description of change
Visit windows were adjusted during the screening 
period to permit for additional time to allow wash-
out of RAAS inhibitors and to obtain GFR results 
from visit 4. 
Rationale for change
Patients should not be taking a RAAs inhibitor 
while taking study treatment.  Patients who can 
safety discontinue the prescribed RAAS inhibitor 
may undergo a 2 week wash-out prior to starting 
visit 2.  GFR from visit 4 must be known prior to 


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proceeding with visit 4a.
Section to be changed
Flow Chart
Description of change
Introduction of a wash-out for patients taking an 
existing RAAS inhibitor.  
Rationale for change
Patients should not be taking a RAAs inhibitor 
while taking study treatment.  Patients who can 
safety discontinue the prescribed RAAS inhibitor 
may undergo a 2 week wash-out prior to starting 
visit 2.
Section to be changed
Flow Chart
Description of change
Visit 4 has been split into two separate visits called 
visit 4 and visit 4a.  Visit 4a includes dispensing 
and administration of ramipril, collection of AEs 
and changes in concomitant therapies. 
Rationale for change
Approximately 10 patients with normofiltration  
will be included after the approval of the 
amendment.  Filtration status from visit 4 must be 
known prior to initiating ramipril therapy.
Section to be changed
Flow Chart Footnotes
Description of change
Footnote 5:  clarified that ketones will only be 
monitored in patients with T1D or patients whose 
diabetes is managed solely with insulin.
Rationale for change
Patients who are at higher risk for KA are required 
to monitor blood ketones whilst participating in the 
trial.
Section to be changed
Flow Chart Footnotes
Description of change
Footnote 9:  Self home blood glucose monitoring is 
only required in patients with diabetes.  Frequency 
of testing for patients with T1D and T2D is 
clarified.
Rationale for change
Obese patients who do not have diabetes are not 
required to monitor their blood sugars unless 
deemed necessary by the investigator.
Section to be changed
Flow Chart Footnotes
Description of change
Footnote 14: Obese patients may not require a 
euglycaemic clamp, based on investigator 
judgment.  If a patient does not require the 
euglycemic clamp, the timing the procedures will 
be maintained per protocol.
Rationale for change
Obese patients who are euglycaemic do not require 
a clamp as their blood glucose will be between 4-6 


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mmol/L.
Section to be changed
Flow Chart Footnotes:
Description of change
Assessment tables were updated to reflect the 
protocol for inulin infusion and iohexol infusion.  
Rationale for change
Iohexol will be utilized to measure GFR after 
amendment 4 due to availability of inulin.
Section to be changed
Flow Chart Footnotes
Description of change
Footnote 15:  reference to euglycaemic clamp was 
removed and replaced with the specific visit 
numbers.
Rationale for change
Not all patients will require a euglycaemic clamp.  
Visits are identified based on visit number.
Section to be changed
Flow Chart Footnotes
Description of change
Footnote 17:  clarified that ramipril will be 
administered at visit 4a.
Rationale for change
Due to the split in visit 4 procedures, the ramipril 
will be administered and dispensed at visit 4a.
Section to be changed
Flow Chart Footnotes
Description of change
Footnote 20:  new footnote added to explain 
requirements for conducting visit 4a.
Rationale for change
GFR values need to be reviewed to ensure that 
hyperfilterer patients are included in the study.  
Section to be changed
Flow Chart Footnotes
Description of change
Footnote 21:  new footnote added to explain the 
wash-out requirement for patients taking a RAAS 
inhibitor.
Rationale for change
Patients should not be taking a RAAs inhibitor 
while taking study treatment.  Patients who can 
safety discontinue the prescribed RAAS inhibitor 
may undergo a 2 week wash-out prior to starting 
visit 2.
Section to be changed
Abbreviations
Description of change
Added abbreviations for chronic kidney disease 
and end stage renal disease.  Removed 
abbreviations for type 1 diabetes hyperfilterer, type 
1 diabetes normofilterer and remote data capture.
Rationale for change
Abbreviations updated based on usage in the 
protocol amendment document.


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Section to be changed
1.1 Medical Background
Description of change
Removed reference to prevalence and management 
of T1D.
Rationale for change
Study population is expanded to include additional 
patient groups including T2D and obese patients.
Section to be changed
1.1 Medical Background
Description of change
Included medical rationale for inclusion of obese 
patients.
Rationale for change
Medical rationale for inclusion of obese patients is 
required. 
Section to be changed
1.2.2.1 Clinical pharmacokinetics – type 2 diabetes 
mellitus
Description of change
PK of empagliflozin in healthy volunteers was 
added.
Rationale for change
Obese patients may not have diabetes and therefore 
PK of empagliflozin in non-diabetic patients is 
relevant.
Section to be changed
2.1 Rationale for Performing the Study
Description of change
Included rationale for inclusion of obese patients.
Rationale for change
Nephropathy may be caused by several factors 
including diabetes as well as obesity.
Section to be changed
2.1 Rationale for Performing the Study
Description of change
Removed reference inclusion of patients who are 
ACEi non-responders and that conditions of 
euglycaemia may not be controlled.
Rationale for change
Study analysis was broadened to analyse patients 
who are hyperfilterers.  Euglycaemic patients may 
not require a euglycaemic clamp.   
Section to be changed
2.2 Trial Objectives
Description of change
References to patients with T1D and controlled 
euglycaemia were removed. 
Rationale for change
Additional patient groups (T2D and obese patients) 
may be enrolled.  Euglycaemic patients may not 
require a euglycaemic clamp.
Section to be changed
2.3 Benefit-risk assessment
Description of change
Added information related to the potential risk for 
inclusion of non-diabetic (euglycaemic) patients in 
the study.
Rationale for change
Additional patient groups (T2D and obese patients) 


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may be enrolled and risk needs to be assessed.
Section to be changed
2.3 Benefit-risk assessment
Description of change
Removed references to T1D-N and T1D-H.
Rationale for change
Additional patient groups (T2D and obese patients) 
may be enrolled.
Section to be changed
3.1 Overall trial design and plan
Description of change
References to controlled euglycaemia were 
removed.
Rationale for change
Euglycaemic clamp is not required for patients who 
are euglycaemic.
Section to be changed
Figure 3.1:1 Trial Design
Description of change
Figure updated to reflect revised visit structure.
Rationale for change
Figure of trial design should reflect the required 
procedures and visits in the protocol.
Section to be changed
3.2 Discussion of Trial Design, Including the 
Choice of Control Group(s)
Description of change
References to type 1 diabetes patients was 
removed.  
Rationale for change
Additional patient groups (T2D and obese patients) 
may be enrolled.  
Section to be changed
3.2 Discussion of Trial Design, Including the 
Choice of Control Group(s)
Description of change
The starting dose of ramipril is recommended to be 
5 mg followed by an up titration rather than 
indicating that the starting dose will be 5 mg.
Rationale for change
To permit the investigator to prescribe a lower dose 
of ramipril based on clinical judgment.
Section to be changed
3.2 Discussion of Trial Design, Including the 
Choice of Control Group(s)
Description of change
Removed reference to hyperfilterer T1D patients.  
Rationale for change
Additional patient groups (T2D and obese patients) 
may be enrolled.  
Section to be changed
3.2 Discussion of Trial Design, Including the 
Choice of Control Group(s)
Description of change
Revised the GFR range for normofiltering patients 
from 90-134 ml/min/1.73m2to 60 to 134 
ml/min/1.73m2.
Rationale for change
Correction made to the range since the entry 


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criteria would allow patients to be entered if the 
eGFR ≥ 60 ml/min/1.73m2 based on creatinine 
measured by the central laboratory at Visit 1
Section to be changed
3.3 Selection of Trial Population
Description of change
Updated the planned number of screened and 
randomized patients from 75 screened patients to 
150 screened patients and 62 randomized patients 
was revised to 74 randomized patients.
Rationale for change
It was determined based on sample size 
recalculation that approximately 74 patients will be 
required.  Based on prior experience screening for 
patients with hyperfiltration, additional patients 
will need to be screened to achieve 74 randomized 
patients. 
Section to be changed
3.3 Selection of Trial Population
Description of change
Enrolment of additional patients with 
normofiltration is capped such that only 40 
normofilterer patients may be randomized into the 
trial.  Screening will continue until the required 
number of hyperfilterer patients are randomized 
into the trial.
Rationale for change
To ensure that the patient population of interest 
(hyperfilterer patients) are randomized into the 
trial.  
Section to be changed
3.3 Selection of Trial Population
Description of change
Changed remote data capture (RDC) to electronic 
data capture (eDC) system.
Rationale for change
The RDC system will no longer be used for data 
capture from site.
Section to be changed
3.3.1 Main Diagnosis for Trial Entry
Description of change
The main diagnosis for trial entry was revised to 
include patients with type 2 diabetes and obese 
patients.
Rationale for change
Nephropathy may be caused by several factors 
including diabetes as well as obesity.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inclusion criteria #2 was revised to permit the 
enrolment of patient with type 2 diabetes or non-
diabetic obese patients into the trial. 
Rationale for change
Nephropathy may be caused by several factors 
including diabetes as well as obesity.


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Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inclusion criteria #3 was clarified to indicate that 
type 1 diabetic patients must either use MDI or 
CSII.
Rationale for change
It is expected that only patients with type 1 
diabetes will utilized insulin therapy to manage 
their diabetes. 
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inclusion criteria #4 was clarified to indicate that 
the HbA1c criteria is relevant for patients with 
either type 1 diabetes or type 2 diabetes.
Rationale for change
It is not expected that non-diabetic obese patients 
will have an HbA1c of 6.5%.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inclusion criteria #5 was clarified to indicate that 
type 1 diabetic patients must have a good 
understanding of their disease.
Rationale for change
Type 1 diabetic patients must have a good 
understanding of their disease and how to manage 
diabetes as a risk mitigation strategy.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inclusion #7, body mass index was revised to 
remove the upper restriction (35 kg/m2).
Rationale for change
Obese patients may have a BMI> 35 kg/m2.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
The footnote that defines women of child bearing 
potential appeared twice.  The duplicate wording 
was removed.
Rationale for change
Duplicate information is redundant.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Exclusion criteria #1 was revised to indicate that 
type 1 diabetic patients should not be treated with 
antihyperglycaemic agents other than insulin.
Rationale for change
Type 2 diabetic patients may be treated with 
antihyperglycaemic agents (except SGLT2 
inhibitors as indicated in exclusion criteria #2).
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Exclusion criteria #10 was revised to exclude 


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patients who required RAAS inhibitors.
Rationale for change
Study will permit patients to undergo a wash-out of 
RAAS inhibitors.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Exclusion criteria #13 was revised to exclude 
patients who had surgical treatment for weight loss 
or aggressive diet and was clarified that patients 
with type 1 diabetes should not use anti-obesity 
drugs within 3 months prior to visit 1.
Rationale for change
Some obese patients may use anti-obesity 
medications.
Section to be changed
4.1.3 Selection of Doses in the Trial
Description of change
Clarified that ramipril treatment should be initiated 
with a starting dose of 5 mg and the dose of 7.5 mg 
q.d. may be provided if this is the maximum 
tolerated dose for a patient.
Rationale for change
Permit the investigator to dose-adjust the ramipril 
therapy so that patients are on maximum tolerated 
dose. 
Section to be changed
Table 4.1.4:1 Oral administration of study 
medications per dose group
Description of change
The week number for the run-in period was 
removed.
Rationale for change
To ensure consistency with the flow chart.
Section to be changed
4.1.4 Drug Assignment and Administration of 
Doses for each Patient
Description of change
Ramipril will first be dispensed at visit 4a rather 
than at visit 4.  The administration of the first dose 
of ramipril should occur at the clinic.
Rationale for change
To ensure consistency with the flow chart.
Section to be changed
4.2.1 Rescue Medication, Emergency Procedures, 
and Additional Treatment(s)
Description of change
Clarified that no anti-hyperglycaemic agents, 
including insulin will be provided as part of the 
study supplies.
Rationale for change
Type 2 diabetic patients may take other anti-
hyperglycaemic agents other than insulin.
Section to be changed
4.2.1 Rescue Medication, Emergency Procedures, 
and Additional Treatment(s)
Description of change
Clarified that management of hypoglycaemia 


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should be done in all patients with diabetes.
Rationale for change
Type 2 diabetic patients are eligible to participate 
under the amendment.
Section to be changed
4.2.1 Rescue Medication, Emergency Procedures, 
and Additional Treatment(s)
Description of change
Clarified that dose adjustment in total insulin dose 
should be performed according to the patient 
HbA1c in patients with type 1 diabetes.  Clarified 
that ketone monitoring is required for patients who 
are insulin dependent (T1D and T2D).
Rationale for change
Insulin dose adjustment is relevant for patients with 
type 1 diabetes and ketone monitoring is also 
relevant for T2D patients.
Section to be changed
4.2.1 Rescue Medication, Emergency Procedures, 
and Additional Treatment(s)
Description of change
Patients with type 1 diabetes need to have a good 
understanding on how to manage their disease.  
Rationale for change
Consistency with protocol inclusion criteria #5.
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Clarified that patients with type 1 diabetes should 
not take antihyperglycaemic agents other than 
insulin.
Rationale for change
Patients with type 1 diabetes must be treated in 
accordance with approved therapies.
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Patients should not take another SGLT2-inhibitor 
during the trial including the follow-up period.
Rationale for change
Patients should not take a prescribed SGLT2 
inhibitor since patients will receive empagliflozin 
during one of the two dosing periods.
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Patients with type 1 diabetes are prohibited from 
taking anti-obesity medications or systemic 
steroids.
Rationale for change
Due to potential increased risk of taking 
medications that may impact metabolism in 
patients with type 1 diabetes.


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Section to be changed
4.2.2.2 Restrictions on diet and lifestyle
Description of change
Revised the days when renal study visits will 
occur.
Rationale for change
To ensure consistency with the updated flow chart.
Section to be changed
5.1.2 Secondary Endpoint
Description of change
Revised the definition of filtration status to 120 
ml/min/1.73m2).
Rationale for change
The primary efficacy subgroup of patients has 
changed from non-responders to hyperfilterers, 
GFR filtration status threshold value lowered as 
lower baseline GFR values expected in this 
subgroup.
Section to be changed
Description of change
Rationale for change
Section to be changed
5.2.1 Hemodynamic measurements
Description of change
Clarified that in all patients blood glucose will be 
routinely monitored to ensure that plasma glucose 
is between 4-6 mmol/L.  A modified clamp 
technique may be used, if required, to maintain 
blood glucose in patients with elevated blood 
sugars and in all patients with diabetes.
Rationale for change
Obese patients who are euglycaemic do not require 
the invasive clamp technique.
Section to be changed
5.2.1 Hemodynamic measurements
Description of change
Clarified that in the first 31 randomized patients 
into the trial inulin will be used to measure GFR.  
However in all remaining patients iohexol will be 
used to measure GFR.  Timing of iohexol infusion 
and blood sample collection as added to the 
protocol.
Rationale for change
Based on the availability of inulin.
Section to be changed
5.3.2.1 Self Blood Glucose Monitoring
Description of change
Clarified that all patients with diabetes will be 
provided with SBGM equipment.  Frequency of 


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testing was defined for patients with type 2 
diabetes.  
Rationale for change
Study will permit the enrolment of patients with 
type 2 diabetes.  SBGM will need to be performed 
in these patients in accordance with clinical 
practice guidelines or as recommended by the 
investigator.
Section to be changed
5.3.2.2 Ketone Monitoring
Description of change
Ketone monitoring is required in patients with T1D 
and patients who are only using insulin for their 
management of diabetes.  Patients who are 
managing type 2 diabetes with oral anti-
hyperglycaemic agents do not need to monitor 
ketones, unless deemed necessary by the 
investigator.
Rationale for change
Patients who manage their diabetes solely with 
insulin are at higher risk of KA and therefore need 
to monitor their ketones routinely.
Section to be changed
Table 5.3.3:1  Safety Laboratory Parameters
Description of change
Clarified that C peptide will be performed in type 1 
diabetic patients only.
Rationale for change
Only relevant in type 1 diabetic patients. 
Section to be changed
5.3.3. Safety laboratory parameters
Description of change
Clarified laboratory parameters to be performed at 
visit 1.  Clarified that prescribed medications 
should be taken as instructed by the prescribing 
physician.  
Rationale for change
Protocol clarification.
Section to be changed
5.3.3. Safety laboratory parameters
Description of change
Inulin and PAH will be analysed by the local lab 
however removed statement that all labs will be 
conducted by the central lab. 
Rationale for change
All lab assessments that are tested by the central 
lab will be included in the lab specification 
document.  
Section to be changed
5.3.6.1 Definitions of adverse events
Description of change
Changed remote data capture (RDC) to electronic 
data capture (eDC) system.
Rationale for change
The RDC system will no longer be used for data 
capture from site.


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Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
Clarified that screening procedures may be 
performed over several days within the screening 
window.
Rationale for change
Protocol clarification.
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
Added information on RAAS wash-out.
Rationale for change
Patients who are taking a RAAS inhibitor and who 
can safety discontinue therapy may under a wash-
out.
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
Patients with type 1 diabetes as well as patients 
who manage their diabetes with inulin should be 
provided with a glucose / ketone meter.
Rationale for change
Risk mitigation strategy for potential KA.
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
Patients should not receive their run-in medication 
until after the GFR results from visit 4 are known.  
Run-in will need to be based on the patients 
screening GFR value.
Rationale for change
To ensure that the required number of hyperfilterer 
patients are entered into the trial. 
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
Clarified that at visit 4a, site staff should obtain the 
ramipril kit number via the IRT system.
Rationale for change
To ensure consistency with the flow chart.
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
GFR that is measured at visit 8 will be monitored 
to ensure that a sufficient number of patients with 
renal hyperfiltration are included into the study.
Rationale for change
To ensure that there are a sufficient number of 
patients with renal hyperfiltration to conduct the 
analysis.
Section to be changed
6.2.2.4 Unscheduled visits during the treatment 
period
Description of change
For patients requiring a dose adjustment to their 
ramipril therapy, the dose of 7.5 mg q.d. or 5 mg 
b.i.d. is recommended.
Rationale for change
Patients should take either 10 mg ramipril or 


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maximum tolerated dose.
Section to be changed
7.1 Statistical Design - Model
Description of change
Added patients with type 2 diabetes or obesity.  
GFR will be assessed under euglycaemic 
conditions.
Rationale for change
Patients with type 2 diabetes and obesity are at risk 
for development of nephropathy.  Therefore these 
patients will also be assessed in the study.  GFR 
measurements will be performed under 
euglycaemic condition however a euglycaemic 
clamp may not be required in obese patients who 
do not have diabetes.
Section to be changed
7.1 Statistical Design - Model
Description of change
Ordering of subgroups was revised to list 
hyperfilterer patients first.
Rationale for change
Main analysis will be performed on patients who 
have renal hyperfiltration at visit 4.
Section to be changed
7.1 Statistical Design - Model
Description of change
Clarified that non-responders and responders are 
sub-groups of hyperfilterers.
Rationale for change
Protocol clarification.
Section to be changed
7.2 Null and alternative hypothesis
Description of change
Population of interest will be patients with renal 
hyperfiltration.
Rationale for change
Due to challenges with identifying patients with 
renal hyperfiltration who are also non-responders 
to ACE inhibition.  
Section to be changed
7.3.1.1 Primary analysis
Description of change
Primary analysis will be performed on the 
hyperfilterer sub-group (based on visit 4 GFR) 
rather than the non-responder sub-group (based on 
visit 8 GFR).
Rationale for change
Due to challenges with identifying patients with 
renal hyperfiltration who are also non-responders 
to ACE inhibition.
Section to be changed
7.3.1.2 Secondary and sensitivity analysis
Description of change
A sensitivity analysis will be performed in the non-
responder sub-group.
Rationale for change
Primary analysis was will be performed on the 
hyperfilterer sub-group.


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Section to be changed
7.3.1.2 Secondary and sensitivity analysis
Description of change
The gradient of the treatment effect will be 
calculated based on randomization baseline GFR 
values that are centred around the mean baseline 
value.  
Rationale for change
Due to challenges with identifying patients with 
renal hyperfiltration who are also non-responders 
to ACE inhibition, a baseline value of 135 
ml/min/1.73m2 no longer expected to be a central 
value.
Section to be changed
7.3.1.2 Secondary and sensitivity analysis
Description of change
Primary endpoint will be analysed separately for 
hyperfilterer patients.
Rationale for change
Consistency with section 7.3.1.1
Section to be changed
7.3.2.1 Primary analysis
Description of change
Definition of filtration status was re-defined as 120 
ml/min/1.73m2 in patients treated with placebo 
added to ramipril or empagliflozin added to 
ramipril.
Rationale for change
The primary efficacy subgroup of patients has 
changed from non-responders to hyperfilterers, 
GFR filtration status threshold value lowered as 
lower baseline GFR values expected in this 
subgroup.
Section to be changed
7.3.2.2 Secondary analysis
Description of change
Secondary analysis will be performed in the non-
responder sub-group with further analysis defined 
in the TSAP.
Rationale for change
Primary analysis will be based on the hyperfilterer 
subgroup.
Section to be changed
7.5 Handling of missing data
Description of change
Patients missing the visit 4 GFR will be omitted 
from the FAS.
Rationale for change
Visit 4 GFR is required to determine if the patient 
is a hyperfilterer.
Section to be changed
7.7 Determination of sample size
Description of change
Details of the effect size from the ATIRMA trial 
were removed. 
Rationale for change
No longer applicable due to the change in the 
primary efficacy subgroup of interest.


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Section to be changed
7.7 Determination of sample size
Description of change
Effect size was assumed to be -15 ml/min/1.73m2
Rationale for change
Study now powered to detect a smaller treatment 
effect that is still considered to be clinically 
meaningful.
Section to be changed
7.7 Determination of sample size
Description of change
Sample size was re-calculated based of the 
hyperfilterer patient population and estimated that 
34 hyperfilterer patients are required.
Rationale for change
Due to challenges with identifying patients with 
renal hyperfiltration who are also non-responders 
to ACE inhibition.
Section to be changed
9.1 Published references
Description of change
The following published reference were added:
P16-01830, R04-2173, P16-06807, R09-2151, 
R18-1327, R18-1328, R18-1329, R18-1330, R18-
1807 and R18-1808.
The following reference was removed from section 
9.1:  R09-2151.
Rationale for change
References were required for the updates made to 
the medical background and benefit-risk 
assessment sections of the protocol amendment.
Section to be changed
9.2 Unpublished references
Description of change
The following unpublished references were added: 
U12-2707-01 and c11963611-01.
Rationale for change
References were required for the updates made to 
the benefit risk assessment section of the protocol 
amendment.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03608483
5.0
clinical-trial-protocol-version-04
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
Author-Clinical Monitor
04 Jul 2018 14:46 CEST
Author-Trial Statistician
04 Jul 2018 15:12 CEST
Approval-Team Member Medicine
04 Jul 2018 16:05 CEST
Approval-Therapeutic Area 
06 Jul 2018 10:11 CEST
Verification-Paper Signature
Completion
06 Jul 2018 13:52 CEST


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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03608483
5.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c08934834-02
BI Trial No.:
1245.100
Title:
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
Including Protocol Amendment 3 [c03608483-05]
Investigational
Product(s):
Jardiance®, empagliflozin
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
09 Oct 2019 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................10
5.
ENDPOINTS .......................................................................................................13
5.1
PRIMARY ENDPOINT .....................................................................................13
5.2
SECONDARY ENDPOINTS.............................................................................13
5.2.1
Key secondary endpoints....................................................................................13
5.2.2
Secondary endpoint.............................................................................................14
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................25
6.1
TREATMENTS...................................................................................................25
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................26
6.3
PATIENT SETS ANALYSED...........................................................................32
6.5
POOLING OF CENTRES .................................................................................34
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................34
6.6.1
Efficacy analysis..................................................................................................34
6.6.2
Safety and other variables..................................................................................35
6.6.3
Missing dates and times......................................................................................35
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................37
7.
PLANNED ANALYSIS......................................................................................41
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........41
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................43
7.3
TREATMENT COMPLIANCE........................................................................44
7.4
PRIMARY ENDPOINT .....................................................................................44
7.4.1
Primary analysis of the primary endpoint........................................................44


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7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint ................................................................................................44
7.4.2.1
Random effects crossover model MMRM1..........................................................45
7.4.2.1.1
Model diagnostics .................................................................................................45
7.4.2.1.2
Examination of potential period effect..................................................................45
7.4.2.1.3
Examination of treatment effect............................................................................45
7.4.2.1.4
Examination of relationship between GFR at baseline and week 4, by 
treatment ...............................................................................................................46
7.4.2.2
Random effects crossover model including the treatment by baseline 
interaction MMRM2.............................................................................................46
7.4.2.3
Random effects crossover model on the natural logarithmic scale MMRM3 ......46
7.4.2.4
Analysis of period one ANCOVA1 ......................................................................46
7.5
SECONDARY ENDPOINT ...............................................................................47
7.5.1
Key secondary endpoint .....................................................................................47
7.5.2
Secondary endpoint.............................................................................................47
7.5.2.1
Primary analysis of the secondary endpoint .........................................................47
7.5.2.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the secondary
7.7
EXTENT OF EXPOSURE.................................................................................49
7.8
SAFETY ANALYSIS..........................................................................................49
7.8.1
Adverse events.....................................................................................................49
7.8.1.1
Assignment of AEs to treatment...........................................................................50
7.8.1.2
Analysis of other significant AEs .........................................................................51
7.8.1.3
AE summaries.......................................................................................................51
7.8.1.4
AEs of special interest...........................................................................................52
7.8.1.5
Other specific adverse events................................................................................55
7.8.1.6
Events qualifying for external adjudication by the Clinical Event Committee ....57
7.8.1.7
AEs while patients were taking wrong medication...............................................58
7.8.2
Laboratory data ..................................................................................................58
7.8.2.1
General laboratory evaluation...............................................................................58
7.8.2.2
Elevated liver enzymes .........................................................................................59
7.8.2.3
Lipid parameters ...................................................................................................59
7.8.2.4
Renal laboratory parameters .................................................................................60
7.8.3
Vital signs.............................................................................................................61
7.8.4
ECG......................................................................................................................61
7.8.5
Others...................................................................................................................61
7.9
SUBGROUP ANALYSIS ...................................................................................61
8.
REFERENCES....................................................................................................63


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LIST OF TABLES
Table 6.1: 1 Definitions of treatment periods ..........................................................................25
Table 6.2: 1 Important protocol deviations..............................................................................27
Table 6.3: 1 Patient sets analysed.............................................................................................33
Table 6.7: 1 Endpoint-specific follow-up period X for assignment to active treatment..........39
Table 6.7: 2 Time windows for scheduled visits......................................................................40
Table 7.1: 1 List of demographic variables at screening and their categorisation...................42
Table 7.1: 2 List of baseline characteristic variables at screening and their categorisation ....42


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ABPM
Ambulatory blood pressure monitoring
ADRNa
Absolute distal sodium reabsorption rate
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse events of special interest
AIx
Augmentation index
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
APR
Absolute proximal fluid reabsorption rate
APRNa
Absolute proximal sodium reabsorption rate
AST
Aspartate transaminase
BHB
Beta-hydroxybutyric acid
BICMQ
BI customised MedDRA query
BMI
Body mass index
BP
Blood pressure
BRPM
Blinded report planning meeting
BSA
Body surface area
cAMP
Cyclic adenosine monophosphate
cGMP
Cyclic guanosine monophosphate
CI
Cardiac index
CLI
Lithium clearance
CNa
Sodium clearance
CO
Cardiac output
CPO
Cardiac power output
CPOI
Cardiac power output index
CS
Compound symmetry
CSII
Continuous Sub-cutaneous Insulin Infusion
CT
Concomitant therapies
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DB
Double-blind


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Term
Definition / description
DDNa
Distal sodium delivery
DKA
Diabetic ketoacidosis
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DTA
Data transfer agreement
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EoT
End of Treatment
ERPF
Effective renal plasma flow
FAS
Full analysis set
FDRNa
Fractional distal sodium reabsorption rate
FENa
Fractional sodium excretion
FELi
Fractional lithium excretion
FF
Filtration fraction
FPG
Fasting plasma glucose
FPR
Fractional proximal fluid reabsorption rate
FWER
Family-wise error rate
GFR
Glomerular filtration rate
HbA1c
Glycated haemoglobin
HRV
Heart rate variability
ICH
International Conference on Harmonisation
IPD
Important protocol deviation
ITT
Intention to treat
LOCF
Last-observation-carried-forward
MAP
Mean arterial pressure
MAR
Missing at random
MDI
Multiple daily injection
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect model repeated measures
NA
Not applicable
O*C
Oracle Clinical
OL
Open label
PD
Protocol deviation


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Term
Definition / description
PG
Plasma glucose
PLi
Plasma lithium
PNa
Plasma sodium
PK
Pharmacokinetics
PPS
Per protocol set
PSTAT
Project Statistician
PT
Preferred term
PWV
Pulse wave velocity
Q1
Lower quartile
Q3
Upper quartile
RBF
Renal blood flow
REML
Restricted maximum likelihood
REP
Residual effect period
RIS
Run-in set
RMSSD
Root mean square successive index
RVR
Renal vascular resistance
SD
Standard deviation
SDNN
Standard deviation of normal-to-normal interval
SE
Standard error
SMQ
Standardised MedDRA query
SOC
System organ class
SV
Stroke volume
SVI
Stroke volume index
SVV
Stroke volume variation
T1D
Diabetes mellitus type 1
T2D
Diabetes mellitus type 2
TFC
Thoracic fluid content
ToC
Table of contents
TPR
Total peripheral resistance
TPRI
Total peripheral resistance index
TS
Treated set
TSAP
Trial statistical analysis plan


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Term
Definition / description
ULi
Urine lithium
UNa
Urine sodium
ULN
Upper limit of normal
unGFR
Uncorrected glomerular filtration rate
UTI
Urinary tract infection
V
Urine flow rate
VI
Vagal index
WHO
World health organisation


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
In July 2019 it was decided to terminate the trial early due to recruitment futility based on the 
inability to find patients with renal hyperfiltration. The study terminates with 31 patients 
randomised and treated. The basis will be CTP Version 4.0 and the analysis plan will be 
driven by the current known status of the study, in terms of the types of patients randomised.
Changes and additions from CTP version 4.0 are outlined in Section 4.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Below are the high level changes that have been made to both the recent versions of the 
protocol and to the deviation from the protocol analyses, following early trial termination in 
July 2019.
High level changes to recent versions of protocol:
The primary patient population was changed from diabetes mellitus type 1 (T1D) only to 
either T1D, diabetes mellitus type 2 (T2D) or obesity in CTP global amendment 3.
The primary analysis population was changed from non-responders to hyperfilterers, i.e. 
patients with a glomerular filtration rate (GFR) ≥135 mL/min/1.73m2 at visit 4 instead of 
visit 8 in CTP global amendment 3. Consequently, a secondary analysis for the primary 
endpoint was planned to be performed on the non-responder subgroup. Further, in the 
secondary analysis of the primary endpoint on all patients in the full analysis set, the gradient 
of the treatment effect will be calculated based on randomization baseline GFR values that are 
centred around the mean baseline value instead of the originally anticipated value of 135 
mL/min/1.73m2, as with the changed population a baseline value of 135 mL/min/1.73m2 is no 
longer considered a central value. In the first 31 patients randomized into the trial inulin was 
used to measure GFR for the primary endpoint analysis. However, as inulin will no longer be 
available, iohexol would have been used to measure GFR for the remaining patients to be 
randomized into the trial.
In CTP global amendment 3 the secondary endpoint filtration status was changed from a 
threshold of < 135 mL/min/1.73m2 to < 120mL/min/1.73m2 in line with the lower baseline 
GFR values expected in the new primary analysis population of hyperfilterers compared to 
non-responders.
The further endpoints “protein intake” and “ratio of GFR to baseline” were removed and the 
further endpoint “24hour urea” was added in CTP global amendment 1.
The further endpoint “urine albumin / creatinine ratio” was removed and the further endpoints 
“glomerular pressure”, “efferent resistance”, “afferent resistance” and “ketones/BHB” were 
added in CTP global amendment 3.
Because the primary analysis population for the primary endpoint was changed in CTP global 
amendment 3, the sample size section was adapted accordingly.
High level changes to TSAP compared to protocol version 4.0:
The main deviation from the protocol-defined efficacy analyses will be on the analysing 
populations. In addition, one planned analysis for the primary endpoint will be removed and 
some further endpoints added. Subgroup analyses are now included for the eight renal 
haemodynamic parameters and for the 24-hour ambulatory blood pressure monitoring 
(ABPM) of systolic blood pressure (BP), diastolic BP and pulse rate.
Since no patients were randomised under the iohexol clearance method, reference will be 
made to inulin clearance only.


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Primary endpoint analysis
Analyses on subgroups of GFR hyperfilterers (n=2), GFR responder (n=2) and GFR non-
responder (n=0) groups are not possible because there are too few patients per group. 
Therefore, it is not possible to test the null hypothesis of the study.
Subsequently, no per protocol set (PPS) will be determined, however, the important protocol 
deviations will still be identified prior to unblinding.
The subgroup of normofilterers (n=29) is very similar to the overall set of patients in the full 
analysis set (FAS) (n=31) and therefore, only the overall set of patients will be analysed. 
For the overall set of patients, all pre-specified analyses will be implemented, except for the 
pre-specified analysis using screening GFR and the screening GFR by treatment interaction. 
Due to the high correlation between screening GFR and baseline (pre-randomisation) GFR, it 
is expected that this would lead to similar findings, compared to the analysis (with 
interaction) using pre-randomisation GFR as baseline.
The assumptions behind the models will be investigated by way of model diagnostics and the 
potential period effect by graphics. Otherwise, the analyses will be as per protocol.
Secondary endpoint analysis
The secondary endpoint of proportion of patients with GFR < 120 mL/min/1. 73m2 will be 
analysed on the FAS only, and with an additional investigation of the GFR status (< 120 vs 
≥120 mL/min/1.73m2) at baseline, given that many of the patients are already
<120 mL/min/1.73m2 at baseline. 
Further endpoint analysis
With regard to the further efficacy endpoints, these will be conducted according to protocol. 
For the planned analyses on the treated set (TS), only the full TS will be used.
Additional further endpoints for Tubular sodium handling will be added:

Fractional sodium excretion (FENa)

Absolute proximal fluid reabsorption rate (APR)

Absolute proximal sodium reabsorption rate (APRNa)

Fractional proximal fluid reabsorption rate (FPR)

Absolute distal sodium reabsorption rate (ADRNa)

Fractional distal sodium reabsorption rate (FDRNa) 


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Additional further endpoints for Cardiovascular and blood pressure parameters will be added:

Cardiac index (CI)

Stroke volume variation (SVV)

Stroke volume index (SVI)

Total peripheral resistance index (TPRI)

Cardiac power output (CPO)

Cardiac power output index (CPOI)

Thoracic fluid content (TFC)
The plan for the analysis of the ABPM parameters will be outlined in the TSAP, as already 
indicated in the protocol. However, additional further endpoints will be created from the data 
collected. Since the ABPM data is collected automatically over a 24 hour period, the 
following endpoints will be determined for each of systolic blood pressure, diastolic blood 
pressure and pulse rate, and grouped accordingly:

24-hourly mean

Night time mean, Day time mean

Awake time mean, Sleep time mean

Trough to peak ratio
Subgroup analysis
There will be descriptive subgroup analyses to investigate the relationship between the 8 renal 
haemodynamic parameters (GFR and the 7 further efficacy endpoints) and screening GFR 
subgroups with categories (≤115 vs >115 mL/min/1.73m2). The value of 115 mL/min/1.73m2
approximately represents the median GFR at screening baseline.
Additionally, the relationship between the 24-hourly mean ABPM parameters (systolic BP, 
diastolic BP and pulse rate) and the two subgroups of baseline body mass index (BMI)
(≤median, >median) and baseline blood pressure (low, high) will be conducted. The specific 
values of low and high will be defined in the subgroup analysis Section 7.9.
For each of these 11 endpoints, a small selection of the main graphical displays will be split 
by these subgroups, to try to identify patterns.
For the renal haemodynamic parameters only, a mixed-effect model repeated measures 
(MMRM) will be conducted.


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5.
ENDPOINTS
This study comprises an open-label run-in treatment period with ramipril, followed by a 
double-blind (DB) treatment period. The DB treatment period further comprises: 1) two 
crossover periods, during which either empagliflozin or placebo is taken in addition to open-
label ramipril (determined according to the randomised treatment sequence); 2) a washout 
period between the two crossover periods, during which only open-label ramipril is taken. 
To avoid all ambiguity, the term “baseline” should not be used without further qualification. 
Measurements taken prior to the start of open-label ramipril treatment will be referred to as 
“screening baseline”. Measurements taken prior to randomisation to one of the two double-
blind treatment sequences will be referred to as “randomisation baseline”. 
Owing to the proposed data capture in this trial (as per CTP flowchart), a need to consider 
separate “period baselines” (i.e. baseline values prior to each of the two crossover periods) in 
all analyses is not envisaged. For select safety laboratory data, period baseline will be used 
where available. 
5.1
PRIMARY ENDPOINT
The primary endpoint is GFR under euglycaemic conditions after 4 weeks of double-blind 
treatment (either empagliflozin or placebo added to ramipril). 
GFR is measured in units of mL/min/1.73m2 (=mL•min-1•1.73m-2). GFR will be calculated by 
the local laboratory using the inulin clearance method and then entered by the study site onto 
the electronic case report form (eCRF). The required euglycaemic conditions are those 
imposed by the clamp used in the trial.
Inulin method for post baseline visits: Two clearance measurements are taken in the 
derivation of each GFR reading, scheduled at 90 minutes and 120 minutes after the start of 
infusion respectively. The mean of the pair of GFR measurements at the relevant 4-week 
visits (visits 11 and 15) will be calculated and used as the primary endpoint value. If only one 
GFR measurement is available, the primary endpoint will be that single value. 
All recorded GFR measurements on the eCRF will be considered eligible for derivation of the 
primary endpoint and will be included in the FAS analysis. However, any values measured 
outside of the visit window (see Table 6.7: 2) will not be used and will therefore not 
contribute to the primary endpoint derivation.
It will be assumed that any GFR values which are technically implausible or otherwise 
incorrect will be removed from the trial database during data cleaning prior to analysis.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.


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5.2.2
Secondary endpoint
The secondary endpoint is filtration status after 4 weeks of double-blind treatment (either 
emplagliflozin or placebo added to ramipril). Filtration status is defined as whether a patient 
has normal filtration status (GFR < 120 mL•min-1•1.73m-2, “yes”), or not
(GFR ≥ 120 mL•min-1•1.73m-2, “no”). GFR is calculated as for the primary endpoint.
No inferential analysis strategy with family-wise error rate (FWER) control is considered. 
Therefore, p-values for the secondary endpoint analysis can just be regarded as a descriptive 
measure of the degree of consistency of observed treatment differences with random 
variability. Likewise, confidence intervals can be regarded as a descriptive measure of the 
plausibility range of the effect size.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
There will be a maximum of eight treatment periods for patients included in this trial: 
screening, Ramipril run-in, ramipril post-treatment, on-treatment (crossover) period 1 (with 
either empagliflozin or matching placebo), treatment x wash-out period, on-treatment 
(crossover) period 2 (with either empagliflozin or matching placebo), treatment x post-
treatment period, and post-study. The definitions of each of these treatment periods are 
defined in Table 6.1: 1 below. (Note: ‘double-blind medication’ refers to either empagliflozin 
or placebo and ‘any study medication’ refers to either ramipril, empagliflozin or placebo.)
Table 6.1: 1 Definitions of treatment periods
Period
Start date
End date
Screening
Informed consent
Start date of open-label ramipril run 
in period – 1 day
Ramipril run-in
First administration of open-
label Ramipril
Start date of DB on-treatment 
period 1 – 1 day, or, Date of last 
intake of open-label ramipril + x 
(for those patients who were not 
treated with DB medication)
Ramipril post treatment#
Date of last intake of open-
label ramipril + x + 1
Last study contact.
On-treatment period 1 
‘Period 1’ or
‘Empa 25mg’ or
‘Placebo’
Date of first administration of 
first DB medication
Date of last administration of first 
DB medication + x
Treatment x washout
‘Empa 25mg washout’ or
‘Placebo washout’
Date of last intake of first DB
medication + x + 1
Start date of second DB on-
treatment period – 1 day. Date is 
not defined for patients who did not 
receive DB medication in period 2
On-treatment period 2 
‘Period 2’ or
‘Empa 25mg’ or
‘Placebo’
Date of first administration of 
second DB medication
Date of last administration of 
second DB medication + x
Treatment x post treatment
‘Empa 25mg post treatment’ or
‘Placebo post treatment’
Date of last administration of 
DB medication + x + 1 day
Date of last study contact + 1 day
Post study
Date of last study contact + 1 
day
Date of trial database lock. Date is 
not defined for a patient that is lost 
to contact whilst still receiving 
study medication.
For efficacy, x=1 day, for AE x=7 days and for laboratory parameters x=3 days as defined in Section 6.7.
# This time period is defined only for patients treated with open label ramipril but not DB medication (and 
therefore not in the TS).


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For certain efficacy and safety analyses, as well as for laboratory data, measurements will still 
be considered on-treatment during a follow-up period of e.g. X = 7 days (see Section 6.7).
This will be applied programmatically where needed and not used in trial database set up; for 
the latter X = 0 will be used.
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to
treatment groups, i.e. patients will be analysed as randomised.
Safety analyses will assign patients to the treatment group as treated. If a patient erroneously 
receives the wrong trial medication, the patient will be analysed according to the actual trial 
medication received. In addition, AEs with an onset during the time of the incorrect study
treatment will be tabulated and listed separately.
The open-label ramipril run-in period will be labelled as the single treatment arm “OL 
Ramipril” on relevant outputs. 
The first and second double-blind on-treatment periods will be labelled “Empa 25mg” and  
“Placebo” according to the medication assigned to or taken in that period  (note: the additional 
background ramipril will not, therefore, form part of the double-blind treatment labels).
Demographic and baseline summaries will be presented by assigned treatment sequence, 
which will be labelled as “Empa25/Pbo” and “Pbo/Empa25” respectively. On these 
summaries a “Total” column will be presented, which is the sum of the number of patients in 
the two treatment sequence columns.
In general, on efficacy and safety tables presenting double-blind treatment, a “Total” column 
will not be added, noting in any case  that for a crossover design, “Total” is not the sum of the 
number of patients displayed under “Empa 25mg” and “Placebo”. 
A limited number of exploratory outputs may also display the crossover period as well as the 
double-blind treatment. For this purpose, the labels used will be “Period 1” and “Period 2”.
6.2
IMPORTANT PROTOCOL DEVIATIONS
There are two aspects that qualify a deviation of the protocol to be important (IPDs):
First, there are PDs that potentially affect the rights or safety of study patients. In this case,
the sponsor needs to react immediately to such PDs to prevent recurrence. In most cases, these 
PDs do not have an impact on whether a patient can be included in an analysis, but they need 
to be described in the report.
Second, a PD can potentially influence the primary outcome measure for the respective
patients in a way that is neither negligible nor in accordance with the study objectives.
Therefore, such PDs potentially affect the main study results and conclusions. This second
category of IPDs forms the basis for the decision of whether a patient does or does not belong 
to an analysis set. Further, for a crossover study, certain categories of IPD may affect only one 
of the two crossover periods, which raises the further possibility of whether the patient should 


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be retained in the analysis set with data from one of the two crossover periods excluded.  
Even though this trial has terminated early and there will be no PPS, this second set of IPDs 
will still be determined.
All other PDs are of minor importance and it is not necessary to describe or list these PDs in 
the integrated clinical trial report (CTR).
The following table defines the different categories of IPDs. The final column describes
which IPDs will be used to exclude patients and/or individual measurements from the analysis 
sets (see also Section 6.3).
Table 6.2: 1 Important protocol deviations
Category/Code
Description
Example/Comment
A
Entrance criteria not 
met
A1
Target indication not 
met
A1.02
Antidiabetic background 
therapy not as required 
for T1D patients
Inclusion criterion 3 not met
No insulin recorded on eCRF for T1D patients
Or
CSII T1D patients: fewer than 3 months experience of using the 
pump prior to Visit 1.
A1.03
No Type 1 Diabetes, 
Type 2 Diabetes or non-
diabetic obesity
Inclusion criterion 2 not met; no diagnosis of T1D, T2D or 
obesity.
A1.05
Time since diagnosis out 
of range for T1D patients
Inclusion criterion 2 not met, with a date of diagnosis < 6 
months prior to Visit 1 for T1D patients.
A2
Inclusion criteria not 
met
A2.01
HbA1c out of range for 
T1D and T2D patients
Inclusion criterion 4 not met
HbA1c <6.3% or > 11.2% at Visit 1 prior to CTP global 
Amendment 3 for T1D patients.
HbA1c <6.5% or > 11.% at Visit 1 after CTP global 
Amendment 3 for T1D and T2D patients
A2.02
Age out of range
Inclusion criterion 6 not met
Age < 18 years at Visit 1.
A2.03
BMI out of range
Inclusion criterion 7 not met
BMI <18.5 kg/m2 or > 35.0 kg/m2 at Visit 1 prior to CTP global 
Amendment 3 for T1D patients.
BMI <18.5 kg/m2 at Visit 1 after CTP global Amendment 3 for 
T1D, T2D or obesity patients.


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Table 6.2 : 1 Important protocol deviations (cont.)
Category/Code
Description
Example/Comment
A2.04
eGFR out of range
Inclusion criterion 8 not met
eGFR < 60 mL/min/1.73m2 according to CKD-EPI formula 
derived using central laboratory creatinine value at Visit 1.
A2.07
BP out of range
Inclusion criterion 9 not met
Average systolic/diastolic BP ≤90 or 60 mmHg, or average 
systolic/diastolic BP  > 140 or 90 mmHg at Visit 1
A3
Exclusion criteria not 
met
A3.02*
Additional background 
therapy
Exclusion criteria 1, 2, 10 or 13 checked
Or any of the following:

Any SGLT-2 inhibitor within 30 days of Visit 1.

Any antihyperglycaemic drug (e.g. metformin, AGI, GLP-1 
analogues, pramlintide, inhaled insulin, pre-mixed insulins 
etc.) except an SGLT-2 inhibitor, subcutaneous basal or 
bolus insulin recorded on eCRF within 3 months prior to 
Visit 1 for T1D patients.

Any concomitant medication at visit 1 known to interfere 
with the RAAS activity and/or renal function based on 
investigator judgment (e.g. ACEi, ARBs, aldosterone 
inhibitors, renin inhibitors etc.).

Weight loss surgery or aggressive diet regimen leading to 
unstable body weight (based on Investigator’s judgment) 3 
months prior to Visit 1.

Treatment with anti-obesity drugs 3 months prior to Visit 1 
for T1D patients.


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Table 6.2 : 1 Important protocol deviations (cont.)
Category/Code
Description
Example/Comment
A3.03*
Relevant concomitant 
diagnoses
Exclusion criteria 3, 4, 5, 6, 8 or 20 checked
Or any of the following:

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*.

Hypoglycaemia unawareness based on Investigator 
judgment or frequent episodes of unexplained 
hypoglycaemia (2 or more unexplained episodes within 3 
months prior to Visit 1)*.

Occurrence of DKA within 3 months prior to Visit 1 or 
until Visit 3.

Acute coronary syndrome (non-STEMI, STEMI and 
unstable angina pectoris), stroke or transient ischaemic 
attack (TIA) within 3 months prior to Visit 1*.

Diagnosis of brittle diabetes*.

Medical history of cancer within the last 5 years (except 
resected basal cell carcinoma)*.
A3.05*
Blood dyscrasias or any 
disorder causing 
haemolysis or unstable 
red blood cell count
Exclusion criterion 16 checked
Or
Relevant diagnosis (e.g. malaria, babesiosis, haemolytic 
anaemia) at Visit 1*.
A3.06
Indication of liver 
disease
Exclusion criterion 9 checked
Or
ALT, AST or alkaline phosphate > 3xULN at Visit 1.
A3.07*
Contraindication to any 
of the drugs in the study 
regime
Exclusion criterion 11 checked
Or
Any contraindication to Altace® (ramipril) per local product 
monograph, including:

History of angioedema

History of haemodynamically relevant bilateral renal artery 
stenosis or unilateral renal artery stenosis in a single kidney

History of hypotension or haemodynamically unstable 
states 

History of hypersensitivity reaction to ramipril or to any 
other ACEi, or to any ingredient in the ramipril formulation


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Table 6.2 : 1 Important protocol deviations (cont.)
Category/Code
Description
Example/Comment
A3.10*
Treatment with protocol 
excluded systemic 
steroids or recent change 
in thyroid hormone dose
Exclusion criteria 14 or 15 checked
Or
Treatment with systemic steroids or planned initiation of such 
therapy at Visit 1 (excluding inhaled or topical use of 
corticosteroids).
Or
Change in dose of thyroid hormone within 6 weeks prior to 
Visit 1 or planned change or initiation of such therapy at Visit 
1*.
A3.11*
Intake of other 
investigational drug in 
another trial within 30 
days prior to intake of 
study medication in this 
trial
Exclusion criterion 19 checked
Or
Intake of another investigational drug in another trial within 30 
days prior to Visit 1*.
Final decision at DBL meeting based on medical judgment.
A3.12*
Specific exclusion 
criterion for pre-
menopausal women 
violated
Inclusion criterion 10 or Exclusion criterion 17 checked
Or
Women who are pregnant, nursing, or who plan to become 
pregnant whilst in the trial*.
A3.13*
Relevant alcohol or drug 
abuse and other 
conditions affecting 
study compliance
Exclusion criterion 18 checked
Or
Alcohol or drug abuse within 3 months prior to Visit 1*.
A3.14*
Any other clinical 
condition unsafe for 
participation that would 
jeopardise patient safety 
while participating in this 
clinical trial
Exclusion criterion 22 checked
Or
Any other clinical condition that, based on Investigator’s 
judgment, would jeopardise patient safety during trial 
participation or would affect the study outcome*.
Final decision at DBL meeting based on medical judgment.
A3.22*
Diagnosis of severe 
gastroparesis
Exclusion criterion 7 checked
Or
Relevant diagnosis recorded as a baseline condition in the 
eCRF.
A3.45*
History of Organ 
Transplant
Exclusion criterion 12 checked
Or
History of organ transplant, including pancreas, pancreatic islet 
cells or renal transplant.
A3.46*
Inability to comply with 
study requirements
Exclusion criterion 21 checked
Or
Patient not able to understand and comply with study 
requirements, based on Investigator’s judgment*.
B
Informed consent
B1
Informed consent not 
available
Inclusion criterion 1 not met
Or
Informed consent date missing.
B2
Informed consent too late
Informed consent date was after Visit 1 date or after any study 
related procedure.


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Table 6.2 : 1 Important protocol deviations (cont.)
Category/Code
Description
Example/Comment
C
Trial medication and 
randomisation
C1
Incorrect trial 
medication
C1.02
Incorrect trial medication 
taken
Wrong double-blind medication taken (different medication 
than the patient was allocated to for that period was taken, i.e. 
drug kit recorded in eCRF is from a different treatment group 
than the drug kit assigned by IRT).
Can only be judged after DBL as requires unblinding 
information.
C1.03*
Incorrect background 
medication dose taken
during run-in
Wrong dosage of ramipril dosage consistently taken during run-
in period.
Final decision at DBL meeting based on medical judgment.
C1.04*
Incorrect background 
medication dose taken
after randomisation
Wrong dosage of ramipril dosage consistently taken during a 
treatment period following randomisation.
Final decision at DBL meeting based on medical judgment.
C2
Randomisation not 
followed
C2.01
Treated without 
randomisation
Patient treated by double-blind medication according to eCRF, 
but not randomised according to IRT.
C3
Non-compliance
C3.01
Non-compliance with 
randomized study drug 
intake
Compliance for empagliflozin or placebo over one or both 4 
week on-treatment periods <80% or >120% (single compliance 
value for each treatment period).
C3.04
Non-compliance with 
background medication 
during run-in period. 
Average ramipril compliance outside of 80-120% during run-in 
period (calculated from two compliance values recorded during 
this period)
C3.05
Non-compliance with 
background medication 
following randomisation
Ramipril compliance outside of 80-120% during a double-blind 
treatment period or the washout period
C4
Medication code 
broken
C4.01*
Medication code broken 
without just cause
Medication code broken whilst on-treatment without valid 
reason*.
Final decision at the DBL meeting based on medical judgment.
D
Concomitant 
medication
D2
Prohibited medication 
use
D2.01*
Use of prohibited 
medication during run-in 
or randomized treatment 
periods
Review of eCRF for contraindicated drugs*.
Final decision at the DBL meeting based on medical judgment.


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Table 6.2 : 1 Important protocol deviations (cont.)
Category/Code
Description
Example/Comment
G3
Other trial specific 
deviation
G3.43*
Errors in measurement of 
randomisation baseline 
GFR value
Protocol for taking clearance measurements (used to calculate 
GFR) not followed and likely to cause significant error in 
measurement of visit 8 value*.
e.g. Unsuccessful euglycaemic clamp.
Final decision on measurement exclusion at the DBL meeting 
based on medical judgment.
G3.44*
Errors in measurement of 
other GFR value
Protocol for taking clearance measurements (used to calculate 
GFR) not followed and likely to cause significant error in 
measurement*.
e.g. Unsuccessful euglycaemic clamp.
Final decision on measurement exclusion at the DBL meeting 
based on medical judgment.
G3.45
Randomisation baseline 
GFR measured outside of 
visit window
Visit 8 GFR measurement taken < 14 days after start of first 
intake of ramipril
G3.46
Treatment period GFR 
measured outside of visit 
window
GFR measurement taken < 14 days after start of treatment 
period 
G3.47
Insufficient washout
The washout period was < 14 days.
*Manual IPD (e.g. IPD that is too complex to program or cannot be detected through the data stored in the trial database).
Some IPDs may need a combination of manual and programmed checks.
6.3
PATIENT SETS ANALYSED
Since this study terminated early, there will be no analyses on the protocol defined subgroups
of hyperfilterers, non-responders, responders and normofilterers. Instead, all patients will be 
analysed together, according to the analysis sets defined below:.

Screened set (SCR):
This patient set includes all patients screened for the trial, with informed consent given 
and who completed at least one screening procedure at Visit 1. This patient set is not 
specifically defined in CTP.

Run-in set (RIS):
The run-in set (RIS) includes all patients from the SCR who were treated with at least 
one dose of study medication (ramipril, empagliflozin, placebo).

Randomised set (RIS):


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This patient set includes all patients from the SCR who were randomized to double-
blind treatment. This patient set is not specifically defined in CTP.

Treated set (TS):
The treated set (TS) includes all patients who were randomised and treated with at 
least one dose of double-blind study medication (empagliflozin, placebo).

Full analysis set (FAS):
This patient set includes all patients who were randomised and treated with at least 
one dose of double-blind study medication (empagliflozin, placebo), and who 
provided a randomisation baseline (visit 8) GFR measurement and at least one post-
randomisation GFR measurement. 

Per protocol set (PPS):
There will be no PPS in this study, however, IPDs will still be defined prior to 
unblinding. IPDs are detailed in Table 6.2: 1.
Table 6.3: 1 below provides an overview of which analysis sets are to be used for the 
various endpoints and analysis of the endpoints.
Table 6.3: 1 Patient sets analysed
Class of Endpoint
Patient 
Set
Subgroup
Primary
Secondary
Further
Safety
Demographics
FAS
All patients
2° Analyses
2° Analyses
X
TS
All patients
X
X
RIS
All patients
One endpoint 
only
X
X


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6.5
POOLING OF CENTRES
This section is not applicable, because the study is performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Based on the different reasons of patients' data missing for different endpoints, various 
methods will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint.
6.6.1
Efficacy analysis
If one of the pair of scheduled GFR measurements (or other similarly recorded data) is 
missing, the endpoint will be defined as the single remaining non-missing value, as specified 
in Section 5.1. If both of the scheduled GFR measurements (or other similarly recorded data) 
are missing, then the endpoint is missing at that visit.
All GFR measurements available on the trial database after data cleaning activities have been 
completed (or other similarly recorded data) will be assumed to be technically plausible and 
eligible for use in the analysis, i.e. will not be set to missing programmatically in any cases. 


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In the event that GFR values (or other similarly recorded data) at a particular visit are outside 
the relevant visit window specified in Section 6.7, the values will be retained in analysis 
datasets, but not used in any analysis.
In the event that randomisation baseline GFR is missing, or both double-blind treatment 
period GFR values are missing, such a patient will be excluded from the FAS by definition, 
and therefore, excluded from all analyses of GFR after 4 weeks of double-blind treatment. 
Since ramipril is given to lower GFR in the run-in period, under no circumstances will a 
missing randomisation baseline GFR be imputed by screening baseline GFR, if randomisation 
baseline GFR is missing after data cleaning activities have been completed.
For all continuous endpoints (including GFR after 4 weeks of double-blind treatment), any 
patient with only one available value will still be included in the mixed model analyses in 
which patient is fitted as a random effect (including the primary analysis of GFR). Missing 
data for one of the crossover periods is implicitly handled in this type of statistical model 
under the missing at random (MAR) assumption. This also means that all patients in the FAS 
will be included in the primary analysis of the primary endpoint. Such a patient will be 
excluded from other analyses in which patient is fitted as a fixed effect. If it is the first 
crossover period where the missing value occurs, such a patient will also be excluded from 
any analysis which only uses data from the first double-blind treatment period.
Since only one value per double-blind treatment period is expected for the endpoints in this 
trial, performing imputations is not needed (e.g. last-observation-carried-forward, LOCF) 
within treatment periods, and it will not be appropriate to perform imputations across 
treatment periods.
For binary endpoints, only patients with data from both double-blind treatment periods 
contribute to the McNemar test statistic. Consequently, patients with missing values for one 
or both periods are implicitly excluded from this analysis.
Rescue medication is not used in this trial, and therefore there is no need to set missing values 
following rescue medication use in any analysis.
Any changes to the above (including the handling of any unresolvable but technically 
implausible GFR values on the trial database) will be documented in the final blinded report 
planning meeting (BRPM) minutes. 
6.6.2
Safety and other variables
Missing safety data will not be replaced. 
6.6.3
Missing dates and times
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (2).
If the date of first period double-blind drug administration is missing, but the patient was 
randomized, the date of first double-blind drug administration will be set to the date of 
randomisation, unless there is evidence that no first period drug was taken at all (e.g. all 


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dispensed drug returned unused). If the date of first double-blind drug administration is 
partially missing with the month and year present, the date of randomisation will be used if it 
was in the same month, and the first day of the month will be used otherwise.
If the date of second period double-blind drug administration is missing, but the patient was 
randomized and completed the washout period, the date of second double-blind drug 
administration will be set to the date of Visit 12, unless there is evidence that no second 
period drug was taken at all (e.g. all dispensed drug returned unused). If the date of second 
double-blind drug administration is partially missing with the month and year present, the 
date of Visit 12 will be used if it was in the same month, and the first day of the month will be 
used otherwise.
If the date of first open-label ramipril administration is missing, but the patient was confirmed 
eligible, the date of first open-label ramipril administration will be set to the date of Visit 4, 
unless there is evidence that no ramipril was taken at all (e.g. all dispensed drug returned 
unused). If the date of first open-label ramipril administration is partially missing with the 
month and year present, the date of Visit 4 will be used if it was in the same month, and the 
first day of the month will be used otherwise.
If the date of a subsequent ramipril dose change is missing but a changed ramipril dose has 
been recorded (including zero dose), it will be imputed by the date of new dose prescription 
(or date of dose interruption) by the site if this can be obtained. If this cannot be obtained, no 
dose change will be assumed. If the date of a subsequent ramipril dose change is partially 
missing with the month and year present, the first day of the month will be used in the 
absence of other information.
All missing times of first drug administration will be imputed as 08:00 in the morning.
Missing drug stop dates will be imputed according to the following principles:

For a missing first period double-blind medication end date, if an End of Treatment 
(EoT) visit is documented only, then the date of the EoT visit will be used. If a Visit 
11 is documented only, or is documented along with an EoT visit or a Visit 15, then 
the date of Visit 11 will be used.  

If the first period double-blind medication end date is incomplete with the month and 
the year present, and the EoT visit and Visit 11 are missing, then the first day of the 
following month will be used.

For a missing second period double-blind medication end date, if an EoT visit is 
documented (in addition to Visit 11), then the date of the EoT visit will be used. If a 
Visit 15 is documented (in addition to Visit 11), then the date of Visit 15 will be used.

If the second period double-blind medication end date is incomplete with the month 
and the year present, and the EoT visit and Visit 15 are missing, then the first day of 
the following month will be used.

If the patient is lost to follow up, or continues in the trial without the expected visit for 
imputation being available at all (e.g. Visit 11 is missing, but Visit 12 and/or Visit 15 


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present), then the date of the previous double-blind drug dispensing visit + longest 
possible treatment duration based on drug supply at that visit + 1 day will be used.

If the ramipril end date is missing, then the date of the previous ramipril dispensing 
visit + longest possible treatment duration based on drug supply at that visit + 1 day 
will be used.

If the ramipril end date is incomplete with the month and year present, then the first 
day of the following month will be used.

If a patient died during the course of the trial and no additional information about drug 
stop date(s) is (are) available, then the date of death will be used as drug stop date(s) 
assuming that the patient took the medication(s) until the day of death.

All other cases need to be assessed by the trial team on an individual basis, trying to 
use the points above as guidance.
If only the year of birth is known, the day and month of birth will be imputed as 01 January.
For partial start and stop dates for concomitant therapies (CT) the following derivations will 
be used to impute 'worst case' values:

If the day of the end date is missing then the end date is set to last day of the month.

If the day and month of the end date are missing then end date is set to 31 December 
of the year.

If the day of the start date is missing the start date is set to first day of the month.

If the day and month of the start date are missing then the start date is set to 01 
January of the year.
For other incomplete date information the midpoint of the possible interval will be used. If 
only the year is present, the day and month will be imputed as 01 July. If year and month is 
present the day will be imputed as 15. If the year is missing, the date will be considered 
missing.
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
To avoid all ambiguity, the term “baseline” should not be used without further qualification. 
Measurements taken prior to the start of open-label ramipril treatment will be referred to as 
“screening baseline” (Visit 4). Measurements taken prior to randomisation to one of the two 
double-blind treatment sequences will be referred to as “randomisation baseline” (Visit 8). 
Randomisation baseline will be at visit 8 and prior to intake of any double-blind study drug. If 
more than one value is recorded at visit 8, the value taken at timepoint -0:05 will be used. 
These will be referenced to explicitly within Section 5.3 Further endpoints.


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Period baseline is the baseline prior to intake of any double-blind study drug, within each of 
the two cross-over periods. For period 1, this is the same as randomization baseline. For 
period 2, this is prior to the intake of double-blind study drug in the second sequence of the 
cross-over. This value has not always been recorded, but is often available for laboratory data.
Time windows for visits will be defined in general relative to the start of the relevant  
treatment period (and not relative to the start of any treatment or to randomisation). The date 
and (where relevant) clock time of the first drug administration for that treatment period will 
be used to determine the visit windows. The notable exception to this is the washout period, 
which is defined based upon the date and time of the last intake of the first period double-
blind medication. 
Measurements taken prior to the first intake of any study medication (ramipril, empagliflozin 
or placebo) will be considered pre-treatment or screening values. Pre-treatment values will be 
assigned to a visit according to the nominal visit number as recorded on the eCRF or as 
provided by the laboratory. Measurements taken after the first intake of ramipril but before 
intake of double-blind medication will be considered run-in or randomization baseline values.
Measurements taken after the last intake of the first double-blind medication but before the 
intake of the second double-blind medication will be considered washout values.
Measurements taken after the first intake of any study medication (ramipril, empagliflozin or 
placebo) will be considered on-treatment values if they have been obtained up to the end of 
the endpoint-specific follow-up period X, as defined in Table 6.7: 1 below. Measurements 
taken after the last intake of study medication and after the endpoint-specific follow-up period 
X will be considered off-treatment values for the treatment in question.


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Table 6.7: 1 Endpoint-specific follow-up period X for assignment to active treatment
Treatment phase
Endpoint(s)
Last day of assignment to treatment 
phase
(days after study drug stop date)
Open-label ramipril run-in
(for patient not 
subsequently randomised)
GFR
HbA1c
1
7
Waist circumference
All other further 
endpoints
7
1
Adverse events
7
Safety laboratory 
measurements
3
Open-label ramipril run-in
(for patient subsequently 
randomised)
GFR
HbA1c
0
0
Waist circumference
All other further 
endpoints
0
0
Adverse events
0
Safety laboratory 
measurements
0
Double-blind treatment 
(both periods)
GFR
HbA1c
1
7
Waist circumference
All other further 
endpoints
7
1
Adverse events
7
Safety laboratory 
measurements
3
Visit window definitions for each treatment phase and time point, based on the relevant 
anchor date to define relative days, are shown in Table 6.7: 2. These visit windows will be 
used in all analyses and summaries of endpoints at specific time points.
Further details on the specific handling of GFR values outside these visit windows, or of 
insufficient washout, with regard to IPDs and PPS analysis are given in Section 6.2.


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Table 6.7: 2 Time windows for scheduled visits 
Time window 
(actual days from 
anchor date)
Nominal 
visit 
numberB
Treatment phase
Visit 
label
Anchor date
Planned 
days
Start
End
8
Run-in
(OL Ramipril)
OL 
Week 4
First ramipril 
administration
28
15
42
11
Period 1
(Empa 25mg/Placebo)
Week 4
First period 1 
medication
administration
28
15
42
12
Washout
NA
Last period 1 
medication
intake
28
15A
42
15
Period 2
(Placebo/Empa 25mg)
Week 4
First period 2 
medication
administration
28
15
42
A  Note that the washout period itself commences on the (X+1)th day after visit 11 so at least (X+1) days 
are required for there to be any washout period at all. 
B  Any values from EOT visits also need to be assigned to the correct treatment phase and appropriate visit 
window, in addition to values from nominal visits 8, 11, 12 and 15.  


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7.
PLANNED ANALYSIS
Disposition of the patient population participating in the trial will be analysed as follows:

Open-label ramipril run-in disposition will be summarized using the screened patients 
set 

Double-blind disposition will be summarized by treatment using the randomized set 
(no “Total” column)

Double-blind disposition per period will also be summarized by treatment sequence 
using the randomized set ( “Total” column will be included).
Disposition summaries by region, country and site are not applicable for this single-centre 
trial.
IPDs during the randomized treatment period will be listed only.
The frequency of patients in different analysis sets will be summarised in total, and by 
treatment sequence.
For in-text tables presenting descriptive analysis of the endpoints and other variables 
(analysed on original scale), the set of summary statistics is: N (number of patients with non-
missing values), mean, standard deviation (SD).
For end-of-text and appendix tables, the set of summary statistics is: N (number of patients 
with non-missing values), mean, SD, min, Q1 (lower quartile), median, Q3 (upper quartile), 
max. 
For the in-text, end-of-text and appendix tables presenting descriptive analysis of the 
endpoints and other variables (analysed on logarithmic scale), the respective summary 
statistics (e.g. gMean, gCV, etc.) will be used.
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Reporting of Clinical Trials and Project Summaries" (3)
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment or treatment sequence (as applicable and unless otherwise specified; all 
patients in the respective patient set whether they have non-missing values or not). 
Percentages will be rounded to one decimal place. The category missing will be displayed 
only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive summaries of the following demographic variables, as measured at screening, will 
be presented:


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Table 7.1: 1 List of demographic variables at screening and their categorisation
Demographic variable at screening
FAS
RIS
Sex
x
x
Race
x
x
Ethnicity
x
x
Age (year)
x
x
*Age categories (18 to 23, 24 to 28, ≥29 years)
x
x
*BMI categories ( <25, 25 to <30, ≥30 kg/m2)
x
x
Height (cm)
x
x
Smoking history
x
x
Alcohol status
x
x
Time since diagnosis of diabetes (year)
x
x
*Time since diagnosis of diabetes (≤5, >5 to ≤10, >10 to ≤25, >25  year)
x
x
eGFR
x
x
*eGFR categories (75 to ≤115, 115 to ≤125, 125 to ≤140 mL/min/1.73m2)
x
x
UACR (mg/g)
x
x
By treatment sequence and Total 
*Definitions of categories are subject to change.
Descriptive summaries of the following variables measured at screening baseline (visit 4) will 
be presented:
Table 7.1: 2 List of baseline characteristic variables at screening and their categorisation
Baseline characteristics at screening
FAS
RIS
GFR (mL/min/1.73m2)
x
x
*GFR categories (≤115, >115 mL/min/1.73m2)
x
x
HbA1c (%)
x
x
*HbA1c categories (<8.5, ≥8.5%)
x
x
FPG (mg/dL)
x
x
*FPG categories (<54, 54 to ≤70, 70 to ≤126, 126 to ≤140, 140 to <200, ≥200 
mg/dL)
x
x
Weight (kg)
x
x
*Weight categories (≤50, >50 to ≤70, 70 to ≤90, >90 kg)
x
x
Waist circumference (cm)
x
x
Systolic blood pressure (bpm)
x
x
Diastolic blood pressure (bpm)
x
x
*Blood pressure categories (SBP≥140 or DBP≥90, SBP<140 and DBP<90)
x
x
By treatment sequence and Total 
*Definitions of categories are subject to change.


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The table on baseline characteristics at screening (Table 7.1: 2) will be reproduced for 
randomization baseline, even though the randomization baseline for the continuous part of 
these variables will also be presented together with the respective further endpoint.
Categories for baseline characteristics are defined in Section 6.4.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant medication use will be summarised by Anatomical-Therapeutic-Chemical 
classification level 3 (ATC3) and preferred name. 
Descriptive summaries of concomitant medication will be presented for:

Screening period (Pre-treatment) for the RIS; by OL ramipril

Run-in period for the RIS; by OL ramipril

Run-in period for the FAS; by treatment sequence and “Total”

Double-blind treatment (including washout) for the FAS; by treatment sequence and 
“Total”

Double-blind treatment (excluding washout) for the FAS; by treatment.
Separate summaries of use of antihypertensives, ASA or lipid lowering drugs will be 
presented:

At screening baseline for the RIS

At randomisation baseline for the FAS; by treatment sequence and “Total”
The displayed categories and defining ATC levels and ATC codes are shown in Table 9.2: 1.
Background pre-existing insulin therapy, including a categorisation of patients using MDI 
versus CSII will be presented for the RIS.
Background total daily insulin dose at screening baseline and randomisation baseline 
respectively will be presented in a summary table in insulin 'unit' and ‘units/kg’ as units of 
insulin per kg body weight at baseline. The table will also display the total daily basal insulin 
dose and the total daily bolus insulin dose at the relevant baseline. The number of insulin 
injections at the relevant baseline will be presented for multiple daily injection (MDI)
patients. These tables will be presented for the RIS and FAS, by treatment sequence and 
“Total” respectively.
Total daily ramipril dose at the start of the open-label ramipril run-in is assumed to be 5mg 
from the data captured (that is, the protocol-specified initial dose 5mg qd), and so will not be 
summarized.
Total daily ramipril dose prior to the start of the double-blind treatment period will be 
summarized for the FAS, by treatment sequence and “Total”. 
Total daily ramipril dose prior to the start of each treatment crossover period will be 
summarized for the FAS, by treatment. 


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Concomitant diseases will be summarised by MedDRA System Organ Class (SOC) and 
preferred term (PT). Both concomitant diseases and relevant diabetic medical history will be 
presented for the RIS and for the FAS, by treatment sequence and “Total” respectively.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
Frequency distribution of patients with an overall open-label ramipril compliance between 
80% and 120% (inclusive) will be reported for the RIS, as well as the patients outside this 
range. Overall compliance for this purpose will be calculated as a weighted average of 
reported OL ramipril compliance (from Visits 5 and 8 on the eCRF).
Frequency distribution of patients with an overall double-blind ramipril compliance between 
80% and 120% (inclusive) will be reported for the FAS, by treatment sequence, as well as the 
patients outside this range. Overall compliance for this purpose will be calculated as a 
weighted average of reported DB ramipril compliance (from Visits 11, 12 and 15 on the 
eCRF).
It is also noted that ramipril dose may change throughout the trial, and therefore the recorded 
ramipril compliance on the eCRF needs to take account of this. Since this is handled using the 
compliance worksheet and instructions given to the site, further details are not given here.
Frequency distribution of patients with a double-blind empagliflozin/placebo compliance
between 80% and 120% (inclusive) will be reported for the FAS, by treatment, as well as the 
patients outside this range. Since a single compliance value is recorded on the eCRF at the 
end of each treatment crossover period (Visit 11/EoT and Visit 15/EoT respectively), this 
single value will be used. No weighted average needs to be calculated.
In the above, where an overall compliance is calculated from more than one visit, if 
compliance is missing at more than one of these visits, then overall compliance will be set to 
missing.
7.4
PRIMARY ENDPOINT
The primary endpoint in this trial is GFR measured after 4 weeks of double-blind treatment 
with either empagliflozin or placebo. 
7.4.1
Primary analysis of the primary endpoint
The protocol planned primary analysis of the primary endpoint in this early terminated trial 
cannot be performed, because data are too sparse in the predefined subgroup of hyperfilterers. 
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint
The primary endpoint will be analysed on all patients in the FAS, only.  This was a predefined 
secondary analysis of the primary endpoint according to the protocol. No further sensitivity 


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analyses are planned. The plan for the analysis of the primary endpoint by subgroups are 
outlined in Section 7.9.
7.4.2.1
Random effects crossover model MMRM1
This predefined secondary analysis of the primary endpoint is analogous to the CTP 
predefined primary analysis of the primary endpoint on the subgroup of hyperfilterers, now 
removed, but just on all patients in the FAS. The aim of this analysis is to investigate the 
treatment effect, whilst adjusting for baseline GFR. 
This is a random effects crossover model, which is a Mixed-Effects Model for Repeated 
Measures (MMRM) for a crossover design using restricted maximum likelihood (REML). 
The model is as described in the CTP Section 7.3.1.1 with a random effect for patient, fixed 
effects for the class variables treatment and period, and a fixed effect for the continuous 
variable randomisation baseline GFR. For ease of terminology, it will be referred to as 
MMRM1. The model structure also gives rise to an implicit compound symmetry covariance 
structure for between patient variance, and consequently within patient and between patient 
variance is assumed to be independent under this model.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.050 (two-sided 95% confidence intervals). The residuals are assumed to have 
a multivariate normal distribution with zero means and covariance matrix of the type specified 
above. 
The primary treatment comparison will be the least squares mean contrast between treatments
(empagliflozin minus placebo). The treatment contrast, its two-sided 95 % confidence interval 
and its p-value will be reported. The model predicted GFR values for each of the baseline 
GFR values and treatment will be presented graphically. Descriptive tables of the GFR values 
by period and treatment and condensed over the two treatment periods will be presented. 
Baseline and change from baseline will be included in the summary.
7.4.2.1.1 Model diagnostics
Model diagnostics will be limited and based on a standard investigation of the studentized 
residuals. 
7.4.2.1.2 Examination of potential period effect
The potential period effect will be examined graphically. Firstly, presenting the mean GFR on 
the y-axis against the period on the x-axis, split by treatment and each of the treatments joined 
by a line. Secondly, the within patient differences will be examined by individual patient 
profiles, one for each treatment sequence. Each plot will present the GFR on the y-axis versus 
the period on the x-axis (patients joined from period 1 to period 2) and the mean GFR at each 
period superimposed.
7.4.2.1.3 Examination of treatment effect
To investigate the treatment effect graphically, a scatter plot will be produced, displaying one 
treatment on the y-axis versus the other treatment on the x-axis, including a 45-degree line 


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and the mean of the two treatments superimposed. In addition, a boxplot showing the 
distribution of the GFR at week 4 by treatment will be included.
7.4.2.1.4 Examination of relationship between GFR at baseline and week 4, by treatment
To investigate the relationship between baseline GFR and GFR at week 4, by treatment, there 
will be a scatter plot with GFR at week 4 on the y-axis and baseline GFR on the x-axis using 
different symbols for each of the two treatments. In addition, GFR at week 4 will be presented 
by subgroups of GFR at baseline, split into three approximately equally sized groups (<107, 
≥107 to <120, ≥120) using boxplots with one display per treatment group. The overall GFR 
(irrespective of baseline) will also be included. 
7.4.2.2
Random effects crossover model including the treatment by baseline interaction 
MMRM2
This was also a predefined secondary analysis of the primary endpoint, on all patients in the 
FAS. It assumes that any treatment effect is linearly dependent upon randomisation baseline 
(visit 8) GFR. This will be done using the analysis model and assumptions described in 
Section 7.4.2.1, with an additional term for the treatment-by-baseline GFR interaction. For 
ease of reference, it will be referred to as MMRM2.
The gradient of the treatment effect with respect to randomisation baseline GFR will be 
estimated, along with its 95% confidence interval and nominal p-value. Estimates for the 
treatment effects and their 95% CIs will be provided for a range of selected randomisation 
baseline GFR values (100, 115 and 130 mL/min/1.73m2). 
The same set of limited model diagnostics as in Section 7.4.2.1.1 will be produced. 
7.4.2.3
Random effects crossover model on the natural logarithmic scale MMRM3
The primary analysis as described in described in Section 7.4.2.1, will be repeated on all 
patients in the FAS with the modification that all GFR measurements (endpoint and 
randomisation baseline values) will be replaced by their natural logarithms (loge). Estimates 
from this model will be back-transformed and the estimate of the treatment effect reported as 
the ratio of geometric means for GFR (empagliflozin/placebo), together with its 95% CI and 
nominal p-value. A value of less than 1 for the ratio of geometric means therefore represents a 
lower mean GFR on empagliflozin compared to placebo.
For ease of reference, this will be referred to as MMRM3.
In order to examine the treatment effect, the same graphical displays (scatter plot and boxplot) 
as defined in Section 7.4.2.1.3 will also be produced on the natural log scale.
7.4.2.4
Analysis of period one ANCOVA1
An ANCOVA analysis will be conducted on the primary endpoint GFR measurements from 
crossover period 1 only, for all patients in the FAS. This will be referred to as ANCOVA(1).


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This is to provide an estimate of the treatment effect that cannot possibly be affected by any 
potential carryover effect, albeit on half of the sample size compared to when both periods are 
included.
The data will be limited to period one data only and the statistical model will include a fixed 
effect for the class variable of first period treatment, and randomisation baseline GFR as a 
linear covariate.
In order to examine the treatment effect within period one, the same graphical displays 
(scatter plot and boxplot) as defined in Section 7.4.2.1.3 will also be produced.
There are no planned sensitivity analyses in this early terminated study.
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoint
The secondary endpoint is filtration status (GFR < 120 mL/min/1.73m2 ) after 4 weeks of 
double-blind treatment with either empagliflozin or placebo. 
7.5.2.1
Primary analysis of the secondary endpoint
The protocol planned primary analysis of the secondary endpoint in this early terminated trial 
cannot be performed, because data are too sparse in the predefined subgroup of hyperfilterers. 
7.5.2.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the secondary
endpoint
The secondary endpoint will be analysed on all patients in the FAS, only.  This was a 
predefined secondary analysis of the secondary endpoint according to the protocol. No further 
sensitivity or subgroup analyses are planned for this endpoint.
The endpoint will be analysed using McNemar’s test, as well as the odds ratio, 95 % CI and 
nominal p-value. A table will be presented showing the number of concordant and discordant 
pairs with each filtration status (<120, ≥120), by treatment. The number of patients omitted 
due to a missing value will be separately recorded. Descriptive statistics showing the 
concordant and discordant pairs will also be produced by the filtration status (<120, ≥120), at 
randomisation baseline and treatment. 
The proportion of patients with each filtration status by both treatment and period will be 
summarised descriptively.


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7.7
EXTENT OF EXPOSURE
A descriptive statistics table with mean, SD, median and range of the number of days a patient 
was on open-label ramipril run-in treatment will be provided for the RIS. The tables will also 
provide the sum of the total time (in years) that all patients pooled together were on open-
label ramipril run-in treatment, as well as descriptive statistics for the mean, minimum and 
maximum total daily ramipril dose for each patient during the run-in period.
Similar tables will be produced for exposure to ramipril across the whole trial for the RIS.
A descriptive statistics table with mean, SD, median and range of the number of days a patient 
was on double-blind treatment will be provided for the TS, by treatment. The tables will also 
provide the sum of the total time (in years) that all patients pooled together were on each 
double-blind treatment. 
A separate listing will be created of any patients that switched treatment at any time during 
double-blind treatment.
In the above summary tables, the number and percent of patients belonging to each 
categorical range of exposure weeks will also be provided using the following cumulative 
categories:
≥ 1 day, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks (for open-label ramipril and double-blind 
treatment)
≥ 1 day, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥8 weeks, ≥ 12 weeks, ≥ 16 weeks (for 
total trial ramipril exposure).
Descriptive statistics for the total daily ramipril dose at the start of each double-blind 
treatment period will be provided for the TS, by treatment. The number and percent of 
patients who received a total daily ramipril dose less than 10 mg for at least one day during 
double-blind treatment (excluding washout period) will also be summarised by treatment.
7.8
SAFETY ANALYSIS
Unless otherwise specified below, all safety analysis specified will be performed separately 
for the open-label ramipril run-in period (on the RIS) and the double-blind treatment period 
(on the TS).
7.8.1
Adverse events
AEs will be coded using the latest version of the MedDRA coding dictionary at database lock.
Any clinically significant new finding in the physical examination, vital signs (pulse 
symptoms) and in the 12-lead ECG starting after visit 4 (start of open-label ramipril run-in) 
will be considered as an AE and will be reported as such.
Unless otherwise specified, the analyses of adverse events will be descriptive in nature and 
analyses of AEs will be based on the number of patients with AEs (not the number of AEs).


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For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on 
the CRF, will be collapsed into AE episodes provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences.

The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence). Exceptions may apply:
o
Genital infection events will not be collapsed if they are representative of 
different types (i.e. fungal balanitis or vulvovaginitis versus other than fungal 
balinitis or vulvovaginitis);
o
Sepsis events will not be collapsed if they are representative of different 
sources of infection (i.e. urinary tract (urosepsis) versus other than urinary 
tract);
o
Severe hypoglycaemia endpoint confirmed by adjudication will not be 
collapsed;
o
Hypoglycamia adverse events will not be collapsed (except in case of 
occurrences with identical onset date, time and glucose value).

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
For further details on summarization of AE data, please refer to (5).
7.8.1.1
Assignment of AEs to treatment
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. To this end, all AEs occurring on or within the respective treatment period will be 
considered ‘treatment-emergent’. For adverse events, the REP is defined as 7 days after the 
last dose of treatment (see Table 6.7: 1). 
Owing to the trial design consisting of an open-label ramipril run-in period and the double-
blind crossover periods, where periods are defined in Table 6.1: 1, adverse events will be 
determined as treatment-emergent according to the following rules:

For the AE summaries of the open-label ramipril run-in period, adverse events will be 
considered “on-treatment” if they lie on or within the run-in period, as defined in Table 
6.1: 1.

For the AE summaries of the double-blind treatment period, adverse events will be 
considered “on-treatment” or ‘treatment emergent’ if they lie on or within on-treatment 
period 1 or on-treatment period 2, as defined in Table 6.1: 1.
AEs occurring on or within the screening period will be referred to as “screening AEs”. 


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AEs occurring during the treatment x washout period will be assigned to “Treatment x 
washout”. 
AEs occurring on or within the treatment x post treatment period will be assigned to 
“Treatment x post-treatment”. 
AEs occurring on or within the post study period will be assigned to ‘Post study’.
AEs occurring on or within the ramipril post treatment period will be assigned to ‘ramipril 
post treatment’.
Section 15 summaries of treatment-emergent AEs in the open-label ramipril run-in period will 
be presented for the RIS. 
Section 15 summaries of treatment-emergent AEs in the double-blind treatment period will be 
presented for the TS, by treatment.
Additional summaries of AEs including off-treatment study periods will be included in 
Appendix 16.1.9.2.
Malignancy and bone fracture events
For malignancy (and respectively bone fracture), in addition to the standard ‘7-day-on-
treatment approach’ detailed above, all malignancy (respectively bone fracture) adverse 
events that occurred between first study drug intake up to study end will be pooled and 
analysed together in Section 15.
7.8.1.2
Analysis of other significant AEs
Other significant AEs will be reported and summarised according to the ICH E3 criterion. 
Thus, AEs classified as 'other significant' will include those non-serious and non-significant 
adverse events with:

‘action taken = discontinuation’ or ‘action taken = reduced’, or

marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
meeting or Blinded Report Planning Meeting.
7.8.1.3
AE summaries
An overall summary of adverse events will be presented for both the open-label ramipril run-
in period and the double-blind treatment period.
The frequency of patients with adverse events will be summarised by treatment, primary 
system organ class and preferred term. AEs will also be reported by intensity. Separate tables 
will be provided for patients with other significant adverse events according to ICH E3, for 
patients with adverse events of special interest (AESI), for patients with serious adverse 
events, for patients with AEs leading to discontinuation, and for patients with drug-related 
AEs.


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The system organ classes will be sorted according to the standard sort order specified by 
EMA; preferred terms will be sorted by frequency (within system organ class).
Appendix 16.1.9.2 will also include an analysis on the frequency of patients with non-serious 
adverse events occurring with incidence in preferred term greater than 5 % by double-blind 
treatment, for disclosure on clinicaltrials.gov website.
7.8.1.4
AEs of special interest 
The protocol defines the following adverse events that for analysis purposes will be 
considered as AESIs:

Decreased renal function: creatinine shows a >= 2 fold increase from baseline and is 
above the upper limit of normal (ULN)

Hepatic injury defined by the following alterations of liver parameters after 
randomization: 
o
An elevation of AST and/or ALT >= 3 fold ULN combined with an elevation 
of total bilirubin >= 2 x ULN measured in the same blood sample
o
An isolated elevation of AST and /or ALT ≥ 5 fold ULN irrespective of any 
bilirubin elevation. 

Diabetic ketoacidosis (DKA)

Severe hypoglycaemic episodes 
For further details on the definition of DKA and severe hypoglycaemic episodes, refer to 
Section 5.3.6.1 of the CTP.
Events of these AESIs are identified through the AE being flagged by the investigator as an 
AESI on the case report form (CRF).
The AESI ‘Decreased renal function’ will be identified by the narrow SMQ “Acute renal
failure: 20000003”. 
This display will be replicated for present serious events and then events leading to 
discontinuation.
Acute renal kidney injury will also be discussed based on the creatinine laboratory data 
increase as detailed in Section 7.8.2.
The AESI ‘Hepatic injury’ will be identified by the narrow SMQs:

Liver related investigations, signs and symptoms: 20000008

Cholestasis and jaundice of hepatic origin: 20000009 

Hepatitis, non-infectious: 20000010 

Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions: 
20000013 


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This display will be replicated for present serious events and then events leading to 
discontinuation.
Further laboratory analyses will support the hepatic evaluation. See Section 7.8.2 for further 
details on elevated liver enzyme analyses.
The AESI ‘Diabetic ketoacidosis (DKA)’ will be identified by using both the CEC confirmed 
ketoacidosis events and the investigator defined Ketoacidosis events.
A frequency table will first summarize the results of the CEC adjudication committee for 
ketoacidosis events (refer to Section 7.8.1.6 for further details on the adjudication process). 
This summary will present the number of patients with CEC:

certain ketoacidosis

potential ketoacidosis

unlikely ketoacidosis

unlikely ketoacidosis but ketosis

unclassifiable events
by worst severity and requirement of hospitalisation. 
A second frequency analysis will be created and will display the characteristics of 
ketoacidosis for patients with CEC certain ketoacidosis. These characteristics will include 
outcome, severity of the worst episode, time to onset of first episode, and lowest blood pH. 
This analysis will be successively repeated for ketoacidosis endpoints considered by the CEC 
as potential, as well as for ketoacidosis endpoints considered by the CEC as certain or 
potential.
Additional analyses will be produced to assess the risk of ketosis. In particular the number of 
patients with any ketosis events (i.e. CEC confirmed unlikely ketoacidosis but ketosis, and 
ketosis events derived from the database that were not trigger events for the adjudication) will 
be summarised. 
Other ketoacidosis endpoints as identified by the investigator will be analysed as above.
Frequency of patients with investigator defined AESI ketoacidosis will in addition be 
tabulated by SOC and PT, as well as using specified trigger search terms for DKA.
The analysis based on specified trigger search terms for DKA will also be restricted to CEC 
certain ketoacidosis, and to CEC potential ketoacidosis.
Two additional analyses will then be performed to distinguish patients with events based on 
trigger terms indicative of ketoacidosis and or diabetic ketoacidosis, from patients with events 
based on trigger terms indicative of acetonaemia.
Serious ketoacidosis will be summarised based on specified trigger search terms for DKA, as 
well as ketoacidosis leading to treatment discontinuation.
An overview table will first summarize the results of the CEC adjudication committee on 
ketoacidosis episodes by worst severity. 


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The CEC certain ketoacidosis episodes will be tabulated by treatment and characteristics of 
ketoacidosis (e.g. outcome, severity, pre-existing factors, blood pH).
The adjudication outcome results on the ketoacidosis episodes will also be summarised based 
on how the episode has been identified for adjudication.
Finally, the number of ketosis episodes will be summarised.
The investigator defined AESI ketoacidosis episodes will be summarised by event 
characteristics, as done on patient level. 
The AESI ‘Severe hypoglycaemic episodes’ will be determined by using severe
hypoglycaemia AEs reported by the investigator as AESI or severe hypoglycemia that has
been confirmed by the adjudication committee. 
Refer to Section 9.3 for further details on the derivation of the severe hypoglycaemia adverse 
event endpoints analysed in this section.
For the analysis of number of patients with severe hypoglycaemia adverse event, a frequency 
table will first summarize the results of the adjudication committee on hypoglycaemic events 
that had been sent to the CEC for adjudication.
Patients with CEC confirmed severe hypoglycaemia will be tabulated by treatment and 
characteristics of hypoglycaemia including minimum glucose level and time to onset of first 
episode. The frequency of severe nocturnal hypoglycaemia AE (i.e. any hypoglycaemia event 
with an onset from 0:00 midnight to 5:59 a.m.) will also be evaluated as part of these 
characteristics. 
Patients with investigator defined AESI severe hypoglycaemia will also be summarised by 
treatment and event characteristics.
Patients with investigator defined AESI severe hypoglycaemia will be then summarised by 
SOC, PT and treatment group. 
Finally, severe hypoglycaemia considered serious or requiring third person assistance will be 
tabulated using the narrow SMQ Hypoglycaemia. This analysis will be repeated for patients 
with CEC confirmed severe hypoglycaemia.
For the analysis of frequency of hypoglycaemic adverse events, the number of CEC 
confirmed severe hypoglycaemic episodes will be first tabulated by treatment and 
characteristics of hypoglycaemia. 
In addition, the severe hypoglycaemic episodes that have been confirmed by the adjudication 
committee will be represented on a graph by hour of the day (from midnight to 11:59 pm). 
The investigator defined AESI severe hypoglycaemic episodes will finally be summarised by 
event characteristics, as done on patient level.


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7.8.1.5
Other specific adverse events
Hypoglycaemia adverse events
In this sub-section, only hypoglycemia reported by the investigator as adverse events will be 
discussed.
Refer to Section 7.8.1.4 for specifications on specific analyses on the AESI severe 
hypoglycaemia.
Refer to Section 9.3 for details on the derivation of the hypoglycaemia adverse event 
endpoints listed below.
Every episode of PG ≤ 70 mg/dL should be documented with the respective time and date of 
occurrence. This includes hypoglycaemia with glucose values < 54 mg/dL and all 
symptomatic and all severe hypoglycaemic events. On the basis of this information the 
hypoglycaemic adverse event will be classified according to the following protocol defined 
categories:

Asymptomatic hypoglycaemia with PG ≤ 70 mg/dL 

Documented symptomatic hypoglycaemia with 54 mg/dL ≤ PG ≤ 70 mg/dL and 
typical symptoms

Documented symptomatic hypoglycaemia with PG < 54 mg/dL and typical symptoms 
and no need for external assistance

Severe hypoglycaemia, event requiring assistance (i.e. the CEC confirmed severe 
hypoglycaemia)
Analysis of number of patients with hypoglycaemia adverse events
The number of patients with hypoglycaemia according to investigator's judgment will be 
tabulated by treatment group.
The frequency of patients with protocol defined hypoglycaemia adverse event will be 
presented by treatment and characteristics of hypoglycaemia. The severity, action taken, 
minimum glucose level of worst episode, and time to onset of first episode will be displayed 
as part of the characteristics. 
Urinary and genital infections
The following additional specific adverse events will also be assessed and tabulated by 
treatment:

Genital infections 

Urinary tract infections (UTI) 


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Genital infections will be identified by: BIcMQ ‘Infections’, narrow sub-search 1.1 ‘Genital 
tract infections predisposed to by glucosuria’.
Urinary tract infections will be identified by: BIcMQ ‘Infections’, narrow subsearch 2.1 ‘UTI 
predisposed by glucosuria’.
The serious genital infection events as well as the genital infection events leading to treatment 
discontinuation will additionally be summarised using the narrow project defined PT list.
Similarly, the serious UTI events as well as the UTIs leading to treatment discontinuation will 
be summarised using the BIcMQ.
A frequency table for complicated urinary tract infections/pyelonephritis/urosepsis where 
‘complicated urinary tract infections’ are defined as serious AEs from the narrow BIcMQ 
UTI, all events included in the sub-BIcMQ pyelonephritis and all events of preferred term 
urosepsis will in addition be provided.
Genital infections based on investigator assessment will additionally be summarised by type 
(fungal balanitis or fungal vulvovaginitis, genital infection other than fungal balanitis or 
fungal vulvovaginits), intensity (mild, moderate or severe),  time to onset of first episode 
(within the first 3 months of treatment or after), duration (<7 days, 7-14 days and >14 days), 
how the event was treated (no treatment, therapy assigned, hospitalisation), treatment (0, 1, 2, 
>2 antimicrobials needed to treat), duration of treatment (≤7 days, >7 days), whether leading 
to discontinuation of treatment, and the number of episodes per patient.
Furthermore, the above mentioned displays on genital infections based on investigator 
assessment will be repeated by the type of infection (fungal balanitis or fungal vulvovaginitis, 
or genital infection other than fungal balanitis or fungal vulvovaginitis).
UTIs based on investigator assessment will additionally be summarised by intensity (mild, 
moderate or severe), time to onset of first episode (within the first 3 months of treatment or 
after), duration (<7 days, 7-14 days and >14 days), anatomical location (upper UTI, lower 
UTI), how the event was treated (no treatment, therapy assigned, hospitalisation), treatment 
(0, 1, 2, >2 antimicrobials needed to treat), duration of treatment (≤7 days, >7 days), whether 
leading to discontinuation of treatment, and the number of episodes per patient.
AESIs of genital infections and UTIs based on investigator assessment will additionally be 
summarised by sex.
Acute pyelonephritis, sepsis, and asymptomatic bacteriuria
The following specific adverse event based on investigator assessment will be tabulated by 
treatment:

Acute Pyelonephritis: patient incidence overall and by intensity, and treatment 
required (0, 1, 2, >2 antimicrobials needed to treat)

Sepsis: patient incidence overall and by source of infection


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
Asymptomatic Bacteriuria: patient incidence overall
Bone fractures 
The frequency of patients with bone fracture will be provided by event characteristics (e.g.
type of fracture, intensity, and time to onset of first fracture). Bone fracture will also be 
displayed by SOC and PT using the BIcMQ. 
Volume depletion
A frequency table of patients with volume depletion will be constructed based on preferred 
terms:

Volume depletion: BIcMQ (sub-BIcMQ origin vascular narrow).
Malignancy
A frequency table will be created for malignancies based on the following narrow SMQs:

Malignancies: The following Sub-SMQs of SMQ Malignancies (20000090) will be 
used: Sub-SMQ Malignant or unspecified tumors (20000091) and Sub-SMQ 
Malignancy related conditions (20000092), excluding PT "Acanthosis nigricans".
7.8.1.6
Events qualifying for external adjudication by the Clinical Event Committee  
An independent external CEC regularly reviews cardiovascular, neurovascular, severe 
hypoglycaemia, hepatic and ketoacidosis events and evaluates whether pre-specified criteria 
for these adjudication endpoints are met. Details on composition of the CEC, responsibilities 
and clinical event definitions are provided in separate CEC charters. Events qualifying for 
adjudication will be selected based on the latest CEC charter versions.
The CEC will be provided with additional, specified background material on the patients with 
these events and perform an assessment of the events. Adjudication assessments will be 
incorporated to the database.
Refer to Section 7.8.1.4 for details on analyses for severe hypoglycamia and for ketoacidosis. 
A frequency table by treatment will be provided for the adjudicated cardiovascular and 
neurological endpoints and for the preferred terms in the specified SMQs of events. A table 
will also be provided for events that were confirmed or non-assessable.
The cardiovascular and neurovascular events qualifying for adjudication will be selected 
based on the following SMQs:

Ischemic heart disease, excluding PTs “Blood creatine phosphokinase abnormal” and 
“Blood creatine phosphokinase increased”

Cardiac failure, excluding PTs “Oedema”, “Oedema peripheral” and “Peripheral 
swelling” unless there are reported as serious events


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
Torsade de pointes / QT prolongation

Cerebrovascular disorders, excluding PT “Fahr's disease”

Further simple preferred terms 

All fatal cases
7.8.1.7
AEs while patients were taking wrong medication 
A listing will be provided for AEs that occurred while a patient was taking the wrong 
medication.
7.8.2
Laboratory data
For continuous safety laboratory parameters standardised and normalised values will be 
derived, as well as the differences to screening baseline for the open-label ramipril run-in 
period, and to both screening and randomisation baselines for the double-blind period. 
If the period baseline for a particular laboratory parameter is available (see definition in 
Section 6.7), then this will be used, in place of the randomization baseline value. Throughout 
the remainder of this section, however, randomization baseline will be referred to.
The process of standardisation and normalisation, as well as standard analyses for safety 
laboratory data, are described in the BI guidance for the Display and Analysis of Laboratory 
Data (4). All analyses considering multiple of times upper limit of normal (ULN) will be 
based on original and not normalized data.
Analysis of further endpoints derived from specific laboratory parameters is described in 
Section 7.6. 
Results of laboratory analyses will be presented based on both SI units and US conventional 
units.
Screening baseline for safety laboratory parameters will be the last available measurement 
before the start of OL ramipril treatment. Randomisation baseline for safety laboratory 
parameters will be the last available measurement before the start of double-blind treatment. 
Unless otherwise specified, laboratory measurements taken up to 3 days after the last 
administration of study drug will be considered as on-treatment (see Section 6.1 and Section 
6.7). 
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings.
7.8.2.1
General laboratory evaluation
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference range at baseline and the 


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last measurement on treatment. Descriptive statistics will be provided by treatment for 
baseline, on-treatment values and for changes from baseline based on normalised values, as 
well as on the basis of standardized values for parameters with an incomplete reference range 
(e.g. lipids).
Descriptive statistics will in addition be calculated for the changes from screening and 
randomisation baselines in haematocrit over time, including during the follow-up period.  In 
particular, statistics will be provided for last-value on-treatment, follow-up, change from 
baseline for last on-treatment value and follow-up, and change from last on-treatment 
assessment to follow-up.
Frequency tables will summarise the number of patients with potentially clinically significant 
abnormalities.
7.8.2.2
Elevated liver enzymes
Special attention will be paid to parameters characterising liver function. These include liver 
enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (AP)) and total bilirubin.
The frequency of the number of patients with AST/ALT elevations >= 3xULN, >= 5xULN, 
>= 10xULN, and >= 20xULN will be displayed.
To support analyses of liver related adverse drug effects, patients with AST and/or ALT 
>=3xULN with concomitant or subsequent TBILI>=2xULN in a 30-day period after
AST/ALT elevation are of special interest. The start of the 30-day time span is triggered by 
each liver enzyme elevation above the defined thresholds. Patients who fulfil one or two of 
the criteria for AST/ALT or total bilirubin elevations above and have no information available 
for the remaining parameter(s) at the same time-point or within the 30-day time window will 
not be listed under "ALT and/or AST >= 3xULN with Total Bilirubin >= 2xULN".
Patients with elevations as defined above by ALT and/or AST, total bilirubin and AP 
combinations, will be summarised and stratified by Alkaline phosphatase < 2xULN and 
>=2xULN. 
Details on patients with elevated liver enzymes will be listed.
7.8.2.3
Lipid parameters
Lipid parameters will be analysed using descriptive statistics only.
Descriptive statistics will be shown over time for the OL ramipril run-in period for the RIS
including change from screening baseline.
Descriptive statistics will be shown over time for the double-blind treatment period by 
treatment for the TS including change from randomisation baseline.


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7.8.2.4
Renal laboratory parameters
Creatinine and eGFR
All calculations for the grading of renal function will be based on the originally measured 
laboratory values and the ULNs given by the laboratory, not on normalised values with BI 
standard reference ranges. 
The glomerular filtration rate will be estimated according to the following CKD-EPI 
creatinine equation, and stored in the trial database:
eGFR (mL/min/1.73 m2) = 141 • min (serum creatinine [µmol/L]/88.4/k, 1)a
     • max (serum creatinine [µmol/L]/88.4/k, 1)-1.209
     • 0.993Age • [1.018 if female] • [1.159, if of African origin]
Where:
- k is 0.7 for females and 0.9 for males,
- a is -0.329 for females and -0.411 for males,
- min indicates the minimum between (serum creatinine/k) and 1,
- max indicates the maximum between (serum creatinine/k) and 1.
- ‘African origin’ is the category ‚Black/African Amer.‘ on the CRF.
For any analysis using eGFR (CKD-EPI, creatinine), the values calculated from the above 
formula using the serum creatinine values from the central laboratory will be used, and not the 
eGFR values provided by the central laboratory.
The following additional rules will apply:

In case of mixed race, if ‘Black or African American’ is one of the patient races, 
eGFR will be by default derived as if the patient is of African origin.

Age will be considered as a discrete variable for the above calculations, and the age 
will be from the same visit as the other variables. The age at a specific visit where 
eGFR is calculated will be derived as follows:  
Age [years] = (date of eGFR laboratory measurement – birth date + 1) / 365.25
A shift table from screening baseline to both last value on treatment and minimum value on 
treatment will be provided for eGFR (CKD-EPI, creatinine) for the OL ramipril run-in period 
using the RIS.
A shift table from randomisation baseline to both last value on treatment and minimum value 
on treatment will be provided for eGFR (CKD-EPI, creatinine) for the double-blind treatment 
period by treatment using the TS.
Descriptive statistics will also be presented for creatinine and eGFR (CKD-EPI, creatinine) 
values over time, and their changes from screening baseline, for the OL ramipril run-in period 
using the RIS.


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Descriptive statistics will also be presented for creatinine and eGFR (CKD-EPI, creatinine) 
values over time, and their changes from both screening and randomisation baselines, for the 
double-blind treatment period by treatment using the TS.
A summary will be created for the OL ramipril run-in period using the RIS of the number of 
patients that experienced a doubling in creatinine on treatment that was out of the normal 
range as compared to screening baseline.
A summary will be created for the double-blind treatment period by treatment using the TS of 
the number of patients that experienced a doubling in creatinine on treatment that was out of 
the normal range as compared to randomisation baseline.
7.8.3
Vital signs
Where not already covered by analyses of further endpoints in Section 5.3.6 and Section 7.6: 
Descriptive summaries of systolic BP, diastolic BP and pulse rate over time, and their changes 
from screening baseline, will be produced for the OL ramipril run-in period using the RIS.
Descriptive summaries of systolic BP, diastolic BP and pulse rate over time, and their changes 
from both screening and randomisation baselines, will be produced for the double-blind 
treatment period by treatment using the TS.
7.8.4
ECG
No analysis is planned for ECG data. Any clinically relevant changes will be reported as AEs.
7.8.5
Others
Not applicable 
7.9
SUBGROUP ANALYSIS
There will be limited subgroup analysis for this study. The combination of endpoints and 
subgroups to be examined is outlined in Table 6.4:1. In general, each endpoint will be 
analysed on the same population as the main analysis. 
Subgroup analysis on renal haemodynamic parameters (8)by screening GFR 
subgroup(MMRMSG)
Descriptive graphical displays will take the form of boxplots and scatter plots. The boxplot 
will investigate the treatment effect alone and the scatter plot will investigate the baseline 
relationship with that particular parameter and treatment. Each will be split by the subgroup, 
which just has two categories.
In order to provide descriptive p-values for the treatment effect within each of the subgroups, 
a random effects crossover model, referred to as ‘MMRMSG’ will be used:
MMRMSG is an interaction model, analagous to MMRM2, but the interaction term will 
be for the treatment by subgroup combination. The model will include treatment, period, 


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baseline of renal parameter being modelled, the screening GFR subgroup and interaction 
of treatment by screening GFR subgroup as fixed effects, and patient as a random effect. 
For each of the subgroups the predicted treatment means and SE by baseline renal 
parameter will be presented graphically. Finally, for each of the two levels of subgroup 
the treatment different with 95% CI will be displayed in the form of a Forest plot. The 
same limited set of model diagnostics as per MMRM1 will be presented.
Subgroup analysis on ABPM 24-hourly mean endpoints by baseline BMI and blood pressure
subgroups
The 3 ABPM 24-hourly endpoints for diastolic BP, systolic BP and Pulse rate will be 
analysed on the 2 subgroups of baseline BMI (≤median, >median) and baseline BP 
(high: Dia BP ≥90 AND Sys BP ≥140, Low: Dia BP<90 OR Sys BP <140). Since this is a lot 
of important information over time, the main mean (SE) plots over time will be reproduced on 
these groups.
For ABPM therefore, the exploration of the data within these subgroups will be descriptive in 
nature, only.
If any of the subgroups have less than 5 patients, then this data exploration will not be 
performed.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9,
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version: 
IDEA FOR CON.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", Version 5.0; 
IDEA FOR CON.
3
001-MCG-159, "Reporting of clinical trials and project summaries", current version;
IDEA FOR CON.
4
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
5
BI-KMED-BDS-HTG-0041: "Handling and summarisation of adverse event data for
clinical trial reports and integrated summaries", current version; KMED.


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10.
HISTORY TABLE
Table 10: 1 History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
09-Oct-2019
None
This is the final TSAP without any 
modification