Clinical Trial Results:
Does Dapaglifozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes?
Summary


EudraCT number 
201600071533 
Trial protocol 
GB 
Global end of trial date 
15 Mar 2019

Results information


Results version number 
v1(current) 
This version publication date 
03 Mar 2020

First version publication date 
03 Mar 2020

Other versions 
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information


Trial identification


Sponsor protocol code 
2015DM07


Additional study identifiers


ISRCTN number 
  
US NCT number 
  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
University of Dundee


Sponsor organisation address 
Ninewells Hospital , Dundee, United Kingdom, DD1 9SY


Public contact 
Chim , University of Dundee, +44 01382 383013, c.c.lang@dundee.ac.uk


Scientific contact 
Lang, University of Dundee, +44 01382 383013, c.c.lang@dundee.ac.uk


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? 
No


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
31 Jul 2019


Is this the analysis of the primary completion data? 
Yes


Primary completion date 
15 Mar 2019


Global end of trial reached? 
Yes


Global end of trial date 
15 Mar 2019


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
To see if Dapagliflozin reduces left ventricular mass more than placebo in participants with type 2 diabetes and left ventricular hypertrophy


Protection of trial subjects 
Not applicable


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
01 Feb 2017


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
Yes


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
United Kingdom: 66


Worldwide total number of subjects 
66


EEA total number of subjects 
66


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
0


Adolescents (1217 years) 
0


Adults (1864 years) 
32


From 65 to 84 years 
34


85 years and over 
0



Recruitment


Recruitment details 
Recruitment took place from February 2017 to May 2018  
Preassignment


Screening details 
1541 invitation letters were sent. Overall 473 (31%) replied that they were interested. 153 were excluded from invitation if eligibility criteria were not met. A total of 320 participants were screened from February 2017 to May 2018. Out of the 320 patients screened 254 were excluded and 66 were recruited  
Period 1


Period 1 title 
Overall Trial (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Investigator, Monitor, Data analyst, Subject  
Blinding implementation details 
Participants were randomised to receive either dapagliflozin (10mg) or placebo in a double blind, randomised fashion. Trial medications were produced and packaged by Astra Zeneca but labelling of the packages were done by Tayside Pharmaceuticals. Randomisation was via TRuST, a GCP compliant webbased system, run by the Tayside Clinical Trials Unit (TCTU), to preserve allocation concealment


Arms


Are arms mutually exclusive 
Yes


Arm title

Dapaglilflozin  
Arm description 
Treatment arm which received dapagliflozin  
Arm type 
Active comparator  
Investigational medicinal product name 
Dapagliflozin


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
10mg Once daily orally for 12 months


Arm title

Placebo  
Arm description 
Participants which received placebo  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
One placebo tablet daily orally





Baseline characteristics reporting groups


Reporting group title 
Overall Trial


Reporting group description 
  



End points reporting groups


Reporting group title 
Dapaglilflozin


Reporting group description 
Treatment arm which received dapagliflozin  
Reporting group title 
Placebo


Reporting group description 
Participants which received placebo 


End point title 
Left ventricular mass change  
End point description 
Change in Left ventricular mass measured by Cardiac MRI


End point type 
Primary


End point timeframe 
12 months




Statistical analysis title 
LVM change difference  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
< 0.018 ^{[1]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
2.82


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.13  
upper limit 
0.51  
Variability estimate 
Standard deviation


Notes [1]  Significant result 


End point title 
Left ventricular mass change indexed to body surface area  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
LVM indexed to BSA change difference  
Statistical analysis description 
Independent T test


Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[2]}  
Pvalue 
= 0.691 ^{[3]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.2


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.21  
upper limit 
0.8  
Variability estimate 
Standard deviation


Notes [2]  Intention to treat [3]  NonSignificant difference 


End point title 
Left ventricular ejection fraction change  
End point description 
Change in left ventricular ejection fraction as measured by cardiac MRI


End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Left Ventricular ejection fraction change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[4]}  
Pvalue 
= 0.415  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.79


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.14  
upper limit 
2.72  
Variability estimate 
Standard deviation


Notes [4]  Intention to treat 


End point title 
End Diastolic Volume  
End point description 
Change in EDV as measured by cardiac MRI


End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
End Diastolic Volume Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.562 ^{[5]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
1.59


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.06  
upper limit 
3.97  
Variability estimate 
Standard deviation


Notes [5]  Not signficant 


End point title 
End Systolic Volume  
End point description 
Change in end systolic volume as measured by cardiac MRI


End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
End Systolic Volume  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.348 ^{[6]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
1.12


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.5  
upper limit 
1.25  
Variability estimate 
Standard deviation


Notes [6]  Not significant 


End point title 
Stoke volume difference  
End point description 
Change in stroke volume as measured by cardiac MRI


End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Stroke volume change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.86 ^{[7]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.47


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.79  
upper limit 
4.85  
Variability estimate 
Standard deviation


Notes [7]  Not significant 


End point title 
Cardiac Output  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Cardiac Output change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.307 ^{[8]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
257.66


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
757.75  
upper limit 
242.43  
Variability estimate 
Standard deviation


Notes [8]  Not significant 


End point title 
Left atrial volume  
End point description 
Change in left atrial volume as measured by cardiac MRI


End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Left atrial volume change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.501 ^{[9]}  
Method 
ttest, 2sided  
Parameter type 
Median difference (final values)  
Point estimate 
1.58


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.24  
upper limit 
3.08  
Variability estimate 
Standard deviation


Notes [9]  Notsignificant 


End point title 
24 Hour systolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
24 hour blood pressure change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
65


Analysis specification 
Prespecified


Analysis type 
superiority ^{[10]}  
Pvalue 
= 0.012 ^{[11]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
3.63


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.44  
upper limit 
0.82  
Variability estimate 
Standard deviation


Notes [10]  Intention to treat analysis [11]  Significant 


End point title 
24 hour diastolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
24 hour diastolic blood pressure change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
65


Analysis specification 
Prespecified


Analysis type 
superiority ^{[12]}  
Pvalue 
= 0.37 ^{[13]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.1


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.2  
upper limit 
1.21  
Variability estimate 
Standard deviation


Notes [12]  Intention to treat analysis [13]  Nonsignificant 


End point title 
Daytime systolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Daytime systolic blood pressure change  
Statistical analysis description 
Intention to treat


Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
65


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.066 ^{[14]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
3.01


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.24  
upper limit 
0.21  
Variability estimate 
Standard deviation


Notes [14]  Nonsignificant 


End point title 
Daytime diastolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Daytime diastolic blood pressure change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
65


Analysis specification 
Prespecified


Analysis type 
superiority ^{[15]}  
Pvalue 
= 0.355  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
1.27


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4  
upper limit 
1.46  
Variability estimate 
Standard deviation


Notes [15]  Intention to treat 


End point title 
Nocturnal systolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Nocturnal systolic blood pressure change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
64


Analysis specification 
Prespecified


Analysis type 
superiority ^{[16]}  
Pvalue 
= 0.017 ^{[17]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
4.38


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.94  
upper limit 
0.81  
Variability estimate 
Standard deviation


Notes [16]  Intention to treat [17]  Significant 


End point title 
Nocturnal diastolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Nocturnal diastolic blood pressure change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
64


Analysis specification 
Prespecified


Analysis type 
superiority ^{[18]}  
Pvalue 
= 0.063  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
2.41


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.95  
upper limit 
0.14  
Variability estimate 
Standard deviation


Notes [18]  Intention to treat 


End point title 
Office systolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Office systolic blood pressure change  
Statistical analysis description 
Intention to treat analysis


Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.08 ^{[19]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
3.49


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.4  
upper limit 
0.43  
Variability estimate 
Standard deviation


Notes [19]  Not significant 


End point title 
Office diastolic blood pressure  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Office diastolic blood pressure change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[20]}  
Pvalue 
= 0.656 ^{[21]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.73


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4  
upper limit 
2.54  
Variability estimate 
Standard deviation


Notes [20]  Intention to treat analysis [21]  Nonsignificant 


End point title 
Visceral adipose tissue volume  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Visceral adipose tissue volume change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
65


Analysis specification 
Prespecified


Analysis type 
superiority ^{[22]}  
Pvalue 
< 0.001  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
679.4


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
998  
upper limit 
360.8  
Variability estimate 
Standard deviation


Notes [22]  Intention to treat analysis 


End point title 
Subcutaneous adipose tissue volume  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Subcutaneous adipose tissue volume change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
62


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.001  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
609.76


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
948.13  
upper limit 
271.28  
Variability estimate 
Standard deviation



End point title 
Weight  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Weight Change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[23]}  
Pvalue 
< 0.001  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
3.77


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.92  
upper limit 
2.61  
Variability estimate 
Standard deviation


Notes [23]  Intention to Treat 


End point title 
BMI  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
BMI Change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[24]}  
Pvalue 
< 0.001  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
1.35


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.77  
upper limit 
0.94  
Variability estimate 
Standard deviation


Notes [24]  Intention to treat analysis 


End point title 
Waist Circumference  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Waist Circumference Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[25]}  
Pvalue 
= 0.001 ^{[26]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
1.83


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.92  
upper limit 
0.75  
Variability estimate 
Standard deviation


Notes [25]  Intention to treat analysis [26]  Significant 


End point title 
Hip Circumference  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Hip Circumference Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[27]}  
Pvalue 
< 0.001 ^{[28]}  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
2.06


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
3.13  
upper limit 
1  
Variability estimate 
Standard deviation


Notes [27]  Intention to treat [28]  Significant 


End point title 
Deceleration time  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Deceleration time change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[29]}  
Pvalue 
= 0.321  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
12.64


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
37.89  
upper limit 
12.6  
Variability estimate 
Standard deviation


Notes [29]  Intention to treat analysis 


End point title 
Early lateral annular tissue doppler velocity  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Early lateral annular tissue doppler velocity  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[30]}  
Pvalue 
= 0.635  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.25


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.78  
upper limit 
1.28  
Variability estimate 
Standard deviation


Notes [30]  Intention to treat analysis 


End point title 
Early septal annular tissue doppler velocity  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Early septall annular tissue doppler velocity  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.503  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.3


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.6  
upper limit 
1.2  
Variability estimate 
Standard deviation



End point title 
Global longitudinal strain  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Global longitudinal strain  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
49


Analysis specification 
Prespecified


Analysis type 
superiority ^{[31]}  
Pvalue 
= 0.024  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
1.43


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.67  
upper limit 
0.19  
Variability estimate 
Standard deviation


Notes [31]  Intention to treat analysis 


End point title 
E/A Ratio  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
E/A Ratio change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[32]}  
Pvalue 
= 0.587  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
0.05


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.05  
upper limit 
0.14  
Variability estimate 
Standard deviation


Notes [32]  Intention to treat analysis 


End point title 
E to e ratio  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
E/e ratio change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[33]}  
Pvalue 
= 0.621  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
0.15


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.4  
upper limit 
1.1  
Variability estimate 
Standard deviation


Notes [33]  Intention to treat analysis 


End point title 
Haemoglobin  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Haemoglobin change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[34]}  
Pvalue 
< 0.001  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
9.51


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.85  
upper limit 
13.18  
Variability estimate 
Standard deviation


Notes [34]  Intention to treat 


End point title 
Haematocrit  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Haematocrit change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[35]}  
Pvalue 
< 0.001  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
2.9


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.84  
upper limit 
3.96  
Variability estimate 
Standard deviation


Notes [35]  Intention to treat analysis 


End point title 
Creatinine  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Creatinine Change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[36]}  
Pvalue 
= 0.123  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
2.26


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.63  
upper limit 
5.14  
Variability estimate 
Standard deviation


Notes [36]  Intention to treat analysis 


End point title 
Estimated GFR  
End point description 

End point type 
Secondary


End point timeframe 
12 Months




Statistical analysis title 
Estimated GFR Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[37]}  
Pvalue 
= 0.217  
Method 
ttest, 2sided  
Parameter type 
Mean difference (net)  
Point estimate 
2.74


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.14  
upper limit 
1.65  
Variability estimate 
Standard deviation


Notes [37]  Intention to treat analysis 


End point title 
Fasting Glucose  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Fasting Glucose Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.002  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
1.68


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.71  
upper limit 
0.65  
Variability estimate 
Standard deviation



End point title 
HbA1c  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
HbA1c  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[38]}  
Pvalue 
= 0.025  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
5.49


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
10.26  
upper limit 
0.71  
Variability estimate 
Standard deviation


Notes [38]  Intention to treat analysis 


End point title 
LDL Cholesterol  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
LDL Cholesterol change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.522  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.06


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.26  
upper limit 
0.13  
Variability estimate 
Standard deviation



End point title 
Total cholesterol  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Total cholesterol  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[39]}  
Pvalue 
= 0.995  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (net)  
Point estimate 
0.07


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.28  
upper limit 
0.15  
Variability estimate 
Standard deviation


Notes [39]  Intention to treat analysis 


End point title 
HDL Cholesterol  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
HDL Cholesterol  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[40]}  
Pvalue 
= 0.031  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
0.08


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0  
upper limit 
0.15  
Variability estimate 
Standard deviation


Notes [40]  Intention to treat analysis 


End point title 
Total Cholesterol to HDL ratio  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Total cholesterol to HDL ratio change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[41]}  
Pvalue 
= 0.085  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
0.21


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.43  
upper limit 
0.01  
Variability estimate 
Standard deviation


Notes [41]  Intention to treat analysis 


End point title 
Triglycerides  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Triglycerides Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[42]}  
Pvalue 
= 0.064  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
0.17


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.41  
upper limit 
0.08  
Variability estimate 
Standard deviation


Notes [42]  Intention to Treat analysis 


End point title 
NTproBNP  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
NTproBNP change  
Comparison groups 
Placebo v Dapaglilflozin


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[43]}  
Pvalue 
= 0.551  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
103.68


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
326.9  
upper limit 
119.54  
Variability estimate 
Standard deviation


Notes [43]  Intention to treat analysis 


End point title 
Leptin  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Leptin Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[44]}  
Pvalue 
= 0.256  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
2931.7


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6901.46  
upper limit 
1038.07  
Variability estimate 
Standard deviation


Notes [44]  Intention to treat analysis 


End point title 
Myeloperoxidase  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Myeloperoxidase Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.172  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
23.02


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
31.05  
upper limit 
77.08  
Variability estimate 
Standard deviation



End point title 
NT pro collagen  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
NT pro collagen change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[45]}  
Pvalue 
= 0.653  
Method 
ttest, 2sided  
Parameter type 
Mean difference (final values)  
Point estimate 
0.46


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.2  
upper limit 
1.29  
Variability estimate 
Standard deviation


Notes [45]  Intention to treat analysis 


End point title 
hsCRP  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
hs CRP Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
66


Analysis specification 
Prespecified


Analysis type 
superiority ^{[46]}  
Pvalue 
= 0.049  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
1296.04


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2650.59  
upper limit 
31.5  
Variability estimate 
Standard deviation


Notes [46]  Intention to treat analysis 


End point title 
Fasting Insulin  
End point description 

End point type 
Secondary


End point timeframe 
12 months




Statistical analysis title 
Fasting Insulin Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
48


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.098  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
3.61


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.97  
upper limit 
0.26  
Variability estimate 
Standard deviation



End point title 
HOMAIR  
End point description 

End point type 
Secondary


End point timeframe 
12 Months




Statistical analysis title 
HOMAIR Change  
Comparison groups 
Dapaglilflozin v Placebo


Number of subjects included in analysis 
48


Analysis specification 
Prespecified


Analysis type 
superiority ^{[47]}  
Pvalue 
= 0.017  
Method 
Wilcoxon (MannWhitney)  
Parameter type 
Mean difference (final values)  
Point estimate 
2.56


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.47  
upper limit 
0.65  
Variability estimate 
Standard deviation


Notes [47]  Intention to treat analysis 


Adverse events information


Timeframe for reporting adverse events 
Adverse events were reported from February 2017 to May 2019


Adverse event reporting additional description 
Adverse events were assessed at every trial visit. Participants were also encouraged to contact myself the Principal investigator for the trial if adverse events developed.
All reported adverse events (AEs) were recorded in detail on an adverse event CRF page.


Assessment type 
Systematic  
Dictionary used for adverse event reporting


Dictionary name 
MedDRA  
Dictionary version 
22.1


Reporting groups


Reporting group title 
Adverse Events Dapagliflozin


Reporting group description 
Adverse events affecting the dapaglilfozin arm  
Reporting group title 
Adverse Events Placebo


Reporting group description 
Adverse events reported in the placebo arm  


Frequency threshold for reporting nonserious adverse events: 1%  



Substantial protocol amendments (globally) 

Were there any global substantial amendments to the protocol? Yes  
Date 
Amendment 

10 Nov 2016 
AM01
Response to MHRA following initial submission
Exclusion criteria updated to say that patients with electrolyte disturbance would be excluded. Patients with a history of DKA to be excluded.
Asked to clarify women of child bearing potential therefore added to protocol that they would be defined as premenopausal women who have not been surgically sterilised or had a hysterectomy, bilateral salpingoophorectomy or bilateral oophorectomy. Women over 45 years old, who had no had a menstrual period for at least 12 months without an alternative cause were considered as post menopausal
Added that women of child bearing age would have a urine pregnancy test pre starting the study and this would be repeated and documented every 4 weeks throughout their participation in the trial
Asked to add that if a participant was commenced on loop diuretics would be discontinued from the trial 

02 Jun 2017 
AMO2
Changed lower limit of HbA1c cut off for inclusion from 53mmol/mol to 48mmol/mol
Changed echocardiographic inclusion criteria to include LVH indexed to Height2.7 in addition to BSA
Changed age cut off for inclusion from 75 to 80 years of age
Increased weight cut off in inclusion criteria to 150kg from 120kg
Added the use of the Scottish primary care research network to recruit participants
Extended recruitment to Fife
Added that participants would undergo an echocardiogram at the end of the study to allow the comparison of diastolic parameters and longitudinal analysis with baseline echocardiogram
Allowed the ability to repeat Sodium and Potassium blood tests if tests at a review visit were abnormal to avoid unnecessary withdrawal. 

12 Dec 2017 
AMO3
Change of CI from Prof Allan Struthers to Prof Chim Lang due to Prof Struthers retiring
Made a change to allow any patients who dropped out whilst recruitment was still underway to be replaced
Change the GFR cut off in inclusion criteria from <60 TO < 45ml/min
Following discussion with the MHRA clarified that adverse reactions with Dapagliflozin did not need to be reported via the yellow card scheme


03 Sep 2018 
Non substantial amendment
AMO4
Reduced follow up from 12months to a minimum of 10 months
In the previous amendment we were allowed to replace any withdrawals during the recruitment period. Protocol therefore changed from 64 participants to 66 as 66 had been recruited at the completion of recruitment 

31 Jan 2019 
AM05
Non substantial amendment
Due to funding we elected to only analyse biomarkers at the beginning and end of the study
Post reading the up to date literature we decided to analyse  Myeloperoxidase, Leptin, hsCRP, NT pro BNP, procollagenIII. This was therefore added to the protocol 

Interruptions (globally) 

Were there any global interruptions to the trial? No  
Limitations and caveats 

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.  
None reported 